NZ626473B2 - Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders - Google Patents

Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders Download PDF

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NZ626473B2
NZ626473B2 NZ626473A NZ62647312A NZ626473B2 NZ 626473 B2 NZ626473 B2 NZ 626473B2 NZ 626473 A NZ626473 A NZ 626473A NZ 62647312 A NZ62647312 A NZ 62647312A NZ 626473 B2 NZ626473 B2 NZ 626473B2
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compound
pyrimido
dihydro
isoquinolinone
diseases
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NZ626473A
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NZ626473A (en
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Luke Jonathan Alvey
Stephen Robert Fletcher
Frederic Gilbert Labeguere
Gregory John Robert Newsome
Laurent Raymond Maurice Saniere
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Galapagos Nv
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Priority claimed from PCT/EP2012/076275 external-priority patent/WO2013092791A1/en
Publication of NZ626473A publication Critical patent/NZ626473A/en
Publication of NZ626473B2 publication Critical patent/NZ626473B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

compound according to Formula (Ia) wherein L1, and G, and R1 are as described herein. The present disclosure relates to compounds that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of formula (Ia). ositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of formula (Ia).

Description

NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS.
FIELD OF THE INVENTION The present invention relates to novel compounds that antagonize GPR84, a G-protein-coupled or that is involved in inflammatory conditions.
The present invention also provides methods for the production of these novel compounds, pharmaceutical compositions sing these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for e inflammatory bowel es (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic ary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.
BACKGROUND OF THE ION GPR84 was recently isolated and characterized from human B cells (Wittenberger et al., 2001, J Mol Biol, 307, 799-813) as the result of an expressed sequence tag data mining strategy, and also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach aimed to identify novel chemokine receptors expressed in neutrophils (Yousefi S et al. 2001 J Leukoc 9, 1045—52).
GPR84 (also known as EX33) ed an orphan GPCR until the identification of medium-chain FFAs with carbon chain lengths of 9-14 as ligands for this receptor (Wang et al. (2006) J. Biol. Chem. 281:3457-64). GPR84 was bed to be activated by capric acid (C10:0), noic acid (C11:0) and lauric acid (C12:0) with potencies of 5 uM, 9 uM and 11 uM, respectively. Two small molecules were also described to have some GPR84 agonist activity: 3,3’ di-indolylmethane (DIM) (Wang et al. (2006) J. Biol.
Chem. 281:3457-64) and embelin ().
GPR84 expression has been shown to be sed in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells, B cells. (Wang et al., 2006, The Journal of Biological Chemistry, 281, 45, 3457-3464, Yousefi et al., 2001, Journal of yte Biology, 69, 1045-1052, Venkataraman and Kuo, 2005, Immunology s, 101, 144-153, W02007/027661 A2). Higher levels of GPR84 were measured in neutrophils and eosinophils than in T-cells and B-cells. GPR84 expression was demonstrated in tissues that may play a role in the propagation of the inflammatory response such as lung, spleen, bone marrow.
For example, in a recent , Du Bois reported the current status of ies for lung interstitial es, such as thic pulmonary fibrosis (IPF). There are almost 300 distinct injurious or inflammatory causes of interstitial lung disease that can result in diffuse lung scarring, and the initial stages of the IPF pathology are very likely to involve inflammation (Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129), and ation therapies involving nflammatory treatment could be advantageously used.
The expression of GPR84 was highly up-regulated in monocytes/macrophages upon LPS stimulation (Wang et al., 2006, The Journal of Biological Chemistry, 281, 45, 3457-3464).
GPR84 knock-out (KO) mice are viable and indistinguishable from wild-type littermate controls (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153). The proliferation of T and B cells in se to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman and Kuo, 2005, Immunology Letters, 101, 3). T helper 2 (Th2) differentiated T cells from GPR84 KO secreted higher levels of IL4, IL5, ILl3, the 3 major Th2 cytokines, compared to wild-type littermate controls. In contrast, the production of the Th1 cytokine, INFy, was r in Th1 differentiated T cells from GPR84 K0 and ype littermate (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153).
[0009] In addition, capric acid, undecanoic acid and lauric acid dose ently increased the ion of interleukin-12 p40 t (IL-12 p40) from .7 murine macrophage-like cells stimulated with LPS. The pro-inflammatory cytokine IL-12 plays a pivotal role in promoting cell-mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 (Th1) responses and inhibiting T helper 2 (Th2) responses. Medium-chain FFAs, through their direct actions on GPR84, may affect Thl/Th2 balance.
[0010] Berry et al. identified a whole-blood 393-gene transcriptional signature for active ulosis (TB) (Berry et al., 2010, Nature, 466, 973-979). GPR84 was part of this whole-blood 393-gene transcriptional signature for active TB indicating a potential role for GPR84 in infectious es.
GPR84 expression was also described in microglia, the primary immune effector cells of the central nervous system (CNS) from myeloid-monocytic origin (Bouchard et al., 2007, Glia, 55:790-800). As observed in peripheral immune cells, GPR84 expression in microglia was highly inducible under inflammatory conditions such as TNFa and IL1 treatment but also notably endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuro-inflammatory processes. Those results suggest that GPR84 would be up-regulated in CNS not only during endotoxemia and multiple sclerosis, but also in all neurological conditions in which TNFa or Ile pro-inflammatory cytokines are produced, including brain injury, infection, Alzheimer’s disease (AD), Parkinson's disease (PD).
GPR84 expression was also observed in adipocytes and shown to be enhanced by inflammatory stimuli aki er al., 2012). The results suggest that GPR84 emerges in adipocytes in response to TNFa from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity, and ore the inhibition of GPR84 activity might be beneficial for the treatment of endocrine and/or metabolic diseases.
Therefore, the present invention provides novel compounds, processes for their preparation and their use in the preparation of a medicament for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic ctive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), nflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic es, and/or diseases involving impairment of immune cell functions.
SUMMARY OF THE INVENTION
[0014] The present invention relates to novel dihydropyrimidinoisoquinolinone compounds that antagonize GPR84, and that are potentially useful for the treatment of inflammatory conditions (for example inflammatory bowel es (IBD), toid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial es (e.g. idiopathic pulmonary fibrosis (IPF))), nflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or es involving impairment of immune cell functions.
The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and s for treating inflammatory conditions (for e atory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. thic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a Formula Ia: CAN | wherein R1 is H, Me, or halo; L1 is absent or is -O-, -S-, or -NR4a-; G is -W-L2-R2, or -W-L3-R3; W is C1_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple bond; L2 is absent or is -O-; R2 is _ H, - CH; alkyl, optionally tuted with one to three groups independently selected from O OH, O halo, O CN, C1_6 alkoxy, C3_7 lkyl, 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and 0, -6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and O phenyl, - C4_7 lkenyl comprising one double bond, - 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S, - C3_7 cycloalkyl optionally tuted With one or more independently selected R5 groups, - 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 , - 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one to three independently ed R6 groups, or - C640 aryl optionally substituted with one or more independently selected R6 groups; L3 is -NR4b-; - C1_4 alkyl substituted With 0 C640 aryl optionally substituted with one or more independently ed R7 groups, or 0 5-10 membered heteroaryl comprising one to three heteroatoms ndently selected from N, S, and O, optionally substituted with one or more independently selected R7 groups, -10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted With one or more independently selected R7 groups, or C640 aryl optionally substituted with one or more independently selected R7 groups; Each R4&1 and R4b is independently selected from H, C14 alkyl, and C3_7 cycloalkyl; - 6 R 1soxoorR; R6 is OH, halo, -N02, C1_6 alkyl optionally substituted with one to three groups independently selected from halo, and C1_6 alkoxy optionally substituted with one to three groups independently selected from halo, and C3_7 cycloalkyl, -C(=O)OR8, -C(=O)NR9R1°, -NHC(=O)-C1_4 alkyl, -CN, phenyl, -O-phenyl, 4-7 membered heterocycloalkyl comprising one to three atoms independently selected from N, O, and S, or -6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S; optionally substituted with one or more indepentently selected C14 alkyl, C1_4 alkoxy, CN, halo, and —C(=0)0R“; R7 is C1_4 alkyl, or halo, and each of R8, R9, R10 and R11 is ndently selected from H and C1_4 alkyl.
In a further aspect, the present ion provides pharmaceutical compositions comprising a nd of the ion, and a pharmaceutical carrier, excipient or t. Moreover, a compound of the t invention useful in the pharmaceutical compositions and treatment methods disclosed herein, is ceutically acceptable as prepared and used. In this aspect of the invention, the pharmaceutical composition may onally comprise further active ingredients le for use in combination with a compound of the invention. [0018 ] In another aspect of the invention, this inventio n provides novel compounds of the invention for use in therapy.
[0019] In a further aspect of the invention, this invention provides a method of treating a mammal susceptible to or afflicted with a ion from among those listed herein, and ularly, such condition as may be associated with aberrant ty of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution, for example inflammatory conditions (for e inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung titial diseases (e.g. idiopathic pulmonary fibrosis ), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, which method comprises administering a eutically effective amount of a nd of the invention, or one or more of the pharmaceutical compositions herein described.
[0020] In a further aspect, the present invention provides a compound of the invention for use in the treatment or prevention of a condition selected from those listed herein, ularly such conditions as may be associated with aberrant ty of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution expression such as matory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or lic diseases, and/or diseases involving ment of immune cell functions.
In additional aspects, this invention provides methods for synthesizing a compound of the invention, with representative synthetic ols and pathways disclosed herein.
[0022] Accordingly, it is an aspect of this invention to provide a compound of the invention, which can modify the activity of GPR84 and thus prevent or treat any conditions that may be causally related thereto.
It is further an aspect of this invention to provide a compound of the invention that can treat or alleviate conditions or diseases or symptoms of same, such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive ary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, mune diseases, endocrine and/or metabolic es, and/or diseases involving impairment of immune cell functions, that may be causally related to the activity and / or sion and/or distribution of GPR84.
[0024] A still further aspect of this invention is to provide pharmaceutical compositions that may be used in the ent or prevention of a variety of disease states, including the diseases associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis ), nflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
Other aspects and advantages will become apparent to those skilled in the art from a consideration of the ensuing ed description.
] The use of a compound according to any one of the preceding aspects in the manufacture of a medicament for the treatment or prophylaxis of inflammatory conditions.
DETAILED DESCRIPTION OF THE INVENTION Definitions
[0026] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and ed scope of the present invention.
When describing the invention, which may include compounds, ceutical itions containing such nds and methods of using such nds and compositions, the following terms, if present, have the following gs unless otherwise indicated. It should also be understood that when bed herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term 'substituted' is to be defined as set out below. It should be further understood that the terms 'groups' and 'radicals' can be considered interchangeable when used herein.
[0028] The articles 'a' and 'an' may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of e 'an analogue' means one analogue or more than one analogue.
'Alkyl' means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
Particular alkyl groups are , ethyl, n-propyl, pyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, nhexyl , and 1,2-dimethylbutyl. Particular alkyl groups have between 1 and 4 carbon atoms. ene' refers to divalent alkane radical groups having the number of carbon atoms specified, in particular 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH 2-CH 2-), the propylene isomers (e.g., -CH2-CH 2-CH 2- and -CH(CH3)-CH 2-) and the like.
'Alkenylene' refers to nt alkene radical groups having the number of carbon atoms and the number of double bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CH=CH-, - CHz-CH=CH-, -C(CH3)=CH-, -C(CH3)=CH-CH2-, -C(CH3)=C(CH3)-, and -CH2-C(CH3)=CH-.
‘Alkynylene’ refers to divalent alkyne l groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CEC-, -CH2-CEC-, and -C(CH3)H-CECH-. y’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C1-C6 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, toxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
‘Amino’ refers to the radical -NH2.
‘Aryl’ refers to a monovalent aromatic arbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes the number of ring members ed.
Particular aryl groups have from 6 to 10 ring members. Where the aryl group is a monocyclic ring system it entially contains 6 carbon atoms. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
‘Carboxy’ refers to the radical -C(O)OH.
[0037] ‘Cycloalkyl’ refers to cyclic non-aromatic hydrocarbyl groups having the number of carbon atoms ed. Particular cycloalkyl groups have from 3 to 7 carbon atoms. Such cycloalkyl groups e, by way of example, single ring structures such as cyclopropyl, cyclobutyl, entyl, cyclohexyl, and cycloheptyl.
‘Cyano’ refers to the radical -CN.
[0039] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (1). Particular halo groups are either fluoro or chloro.
‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfiJr atom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e. g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
‘Heteroaryl’ means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and the number of ring members specified. ular heteraryl groups have 5 to 10 ring members, or 5 to 6 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic ure formed from fiJsed five and six membered rings or two fused six membered rings or, by way of a fithher example, two fiJsed five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. lly the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, ole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, le, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups e but are not limited to pyridine, ne, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, oxazole, benzthiazole, benzisothiazole, isobenzofuran, , isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and lopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, roman, chromene, omene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, oline, ine, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those d from thiophene, pyrrole, benzothiophene, benzofiJran, indole, ne, quinoline, imidazole, oxazole and pyrazine.
Examples of representative heteroaryls e the following: H N N flN/) [“3 N/ OE:N/ N /®© [93N\ CE.” CCN CD:N wherein each Y is ed from >C=O, NH, O and S.
As used herein, the term ‘heterocycloalkyl’ refers to a stable heterocyclic non-aromatic ring and/or rings containing one or more heteroatoms independently selected from N, O and S, fused o wherein the group contains the number of ring members specified. Particular heterocycloalkyl groups have 2012/076275 4-10 ring s or 5 to 7 ring members, or 5 to 6 ring members. The heterocycloalkyl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single atom. In one embodiment, the heterocycloalkyl ring contains at least one ring nitrogen atom. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1- pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. ahydro l), imidazoline, olidinone, oxazoline, thiazoline, 2- pyrazoline, pyrazolidine, zine, and N—alkyl piperazines such as N—methyl piperazine, Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N—alkyl piperidines such as N—methyl piperidine. Particular examples of cycloalkyl groups are shown in the following rative examples: Y YVA/ Y/X YE w [W1 0 Y 1? L? C65 it? Cd/ wherein each W is selected from CH2, NH, O and S; and each Y is ed from NH, O, CO, S02, and S.
‘Hydroxy’ refers to the radical -OH.
[0045] ‘Nitro’ refers to the radical -NOZ.
‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
‘Thiol’ refers to the group -SH.
‘Thioalkoxy’ refers to the group -SR10 where R10 is an alkyl group with the number of carbon atoms specified. In particular thioalkoxy groups where R10 is a C1-C6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, opropoxy, n-thiobutoxy, tert-thiobutoxy, iobutoxy, nthiopentoxy , n-thiohexoxy, and 1,2-dimethylthiobutoxy. ular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular thioalkoxy groups have between 1 and 4 carbon atoms.
As used herein, the term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents.
In a yet further embodiment it refers to one substituent.
One having ry skill in the art of organic sis will recognize that the m number of heteroatoms in a stable, chemically feasible heterocyclic ring, r it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and .
‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the US. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
[0052] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent nd. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, nic acid, hexanoic acid, entanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, ic acid, malic acid, maleic acid, fiimaric acid, tartaric acid, citric acid, c acid, ydroxybenzoyl) benzoic acid, cinnamic acid, ic acid, esulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent nd either is replaced by a metal ion, e. g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, nolamine, triethanolamine, N—methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic fiJnctional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
WO 92791 ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention,which have cleavable groups and become by solvolysis or under physiological ions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N—alkylmorpholine esters and the like. te’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. tional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and r include both iometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and olates.
[0056] ‘Subject’ es humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
‘Effective amount’ means the amount of a compound of the invention that, when stered to a subject for treating a disease, is sufficient to effect such treatment for the e. The “effective amount” can vary depending on the compound, the disease and its ty, and the age, weight, etc., of the subject to be treated. nting’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or er (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the stration of vaccines; the administration of low lar weight n to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[0060] ‘Treating’ or ment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or ng the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ing’ or ‘treatment’ refers to ting the disease or disorder, either physically, (e.g., stabilization of a discernible m), physiologically, (e.g., stabilization of a physical parameter), or both. In a fithher embodiment, ing” or “treatment” relates to slowing the progression of the disease.
As used herein the term ‘inflammatory condition(s)’ refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, le idiopathic arthritis, vasculitis, psoriasis, gout, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn’s e, ulcerative colitis), and endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e. g. chronic cardiac failure). ularly the term refers to rheumatoid tis, allergic airway disease (e.g. asthma) and atory bowel diseases.
As used herein, the term ‘infectious es’ refers to bacterial infectious diseases and includes but is not limited to conditions such as sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, dia, Shigella, or enterobacteria s.
As used herein the term ‘autoimmune disease(s)’ refers to the group of diseases including obstructive airways disease (including conditions such as COPD (Chronic obstructive ary disease)), psoriasis, asthma (e.g intrinsic asthma, extrinsic , dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, ing bronchial asthma, systemic lupus erythematosus (SLE), le sclerosis, type I diabetes mellitus and complications associated ith, atopic eczema (atopic itis), contact dermatitis and further eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic l sclerosis. Particularly the term refers to COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
As used herein the term ‘endocrine and/or lic disease(s)’ refers to the group of conditions involving the body’s over- or under-production of certain hormones, while metabolic disorders affect the body’s ability to process certain nutrients and vitamins. Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, es of the adrenal glands (including Cushing’s syndrome and Addison’s e), and ovarian dysfunction (including polycystic ovary syndrome), among others. Some examples of metabolic disorders include cystic fibrosis, ketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
As used herein, the term ‘diseases involving impairment of immune cell functions’ includes conditions with symptoms such as recurrent and drawn out viral and bacterial infections, and slow recovery.
Other invisible symptoms may be the inability to kill off parasites, yeasts and ial pathogens in the intestines or throughout the body.
As used herein the term ‘neuroinflammatory conditions’ refers to diseases or disorders characterized by abrupt neurologic deflcits associated with inflammation, demyelination, and axonal damage, and includes but is not limited to conditions such as Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune alomyelitis.
‘Compound(s) of the invention’, and equivalent sions, are meant to e compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. rly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and es, where the context so permits.
When ranges are referred to herein, for example but without limitation, C1_6 alkyl, the citation of a range should be considered a representation of each member of said range.
[0069] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid ive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of gs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed ides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this ion are particularly useful prodrugs. In some cases it is desirable to prepare double ester type gs such as xy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C1 to Cg alkyl, and substituted or unsubstitutedC6_10 aryl, esters of the compounds of the ion.
As used herein, the term ‘isotopic variant’ refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound For e, an ‘isotopic t’ of a compound can contain one or more non-radioactive es, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (ISN), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue bution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. r, compounds may be prepared that are substituted with positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
All isotopic variants of the nds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
It is also to be tood that compounds that have the same molecular formula but differ in the nature or ce of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’.
Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’. isomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an tric , for e, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture f. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of TE electrons and an atom (usually H). For example, enols and s are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
Tautomeric forms may be relevant to the attainment of the l chemical reactivity and biological activity of a compound of interest.
[0076] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as dual (R)- or (S)— stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the ication and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the ination of stereochemistry and the separation of stereoisomers are well-known in the art.
It will be appreciated that compounds of the invention may be lized to yield biologically active metabolites.
THE COMPOUNDS The present invention relates to novel compounds that antagonize GPR84 and that may be useful for the ent of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic es, and/or diseases involving impairment of immune cell functions.
The present invention also provides methods for the tion of the nds ofthe invention, pharmaceutical itions comprising the compounds of the invention and s for treating diseases involving inflammatory conditions (for example inflammatory conditions (for e inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, by administering a compound of the invention. A compound of the invention is an inhibitor of GPR84.
Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a Formula Ia: CAN | wherein R1 is H, Me, or halo; L1 is absent or is -O-, -S-, or -NR4a-; G is -W-L2-R2, or -W-L3-R3; W is C1_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple bond; L2 is absent or is —O-; R2 is _ H, - CH; alkyl, optionally substituted with one to three groups independently selected from o OH, 0 halo, WO 92791 0 CN, 0 C1_6 alkoxy, o C3_7 cycloalkyl, o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O, o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and o phenyl, - C4_7 cycloalkenyl comprising one double bond, - 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S, - C3_7 lkyl optionally substituted With one or more independently selected R5 groups, - 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 groups, - 5-10 ed heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, ally substituted With one to three independently selected R6 groups, or - C640 aryl optionally tuted with one or more ndently selected R6 groups; L3 is -NR4b-; R3 is - C1_4 alkyl substituted with 0 C640 aryl optionally substituted with one or more independently selected R7 groups, or 0 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R ndently selected R7 groups, 5-10 membered heteroaryl comprising one to three heteroatoms ndently selected from N, S, and O, optionally substituted With one or more independently selected R7 groups, or - C640 aryl optionally substituted with one or more independently selected R7 groups; Each R4&1 and R4b is independently selected from H, C14 alkyl, and C3_7 cycloalkyl; R5 is oxo or R6; R6 is - OH, - halo, - -NOZ, - C1_6 alkyl ally substituted with one to three groups independently selected from halo, and OH, C1_6 alkoxy optionally substituted with one to three groups independently selected from halo, and C3_7 cycloalkyl, -C(=O)OR8, -C(=O)NR9R1°, -NHC(=O)-C1_4 alkyl, -CN, -O-phenyl, 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or -6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S; optionally substituted with one or more indepentently selected C14 alkyl, C1_4 alkoxy, CN, halo, and —C(=0)0R“; 7 is C1_4 alkyl, or halo; and each of R8, R9, R10 and R11 is ndently ed from H and C1_4 alkyl.
In a further embodiment, a compound of the invention is disclosed having a Formula lb: wherein R1, L1 and G are as previously described.
[0083] In yet a fithher embodiment, a compound of the invention is sed having a Formula Ic: CAN I L1/G wherein R1, L1 and G are as previously described.
In one embodiment, the compound of the invention is according to Formula Ia, lb or Ic, wherein R1 is Me, F, or C1.
In one embodiment, the compound of the ion is according to Formula Ia, lb or Ic, n R1 is H.
In one embodiment, the compound of the ion is according to Formula IIa, IIb, or Ho: 0 o o /0 be E 5/0 N/l N/l N/l OA\N OA\N OA\N m—W m—W M—W 1m 1m 1m wherein L1, and R2 are as decribed previously.
In one embodiment, the compound of the invention is according to Formula IIIa, IIIb, or IIIc: o o /0 K/o o/\O O O L1WQR qw Ma nm 1% wherein L, W, L2, and R2 are as decribed previously.
In one embodiment, the compound of the invention is according to Formula IVa, IVb, or No: 09., Lo /' 09., o N o N LTW LTW1§R3 /W\ ,R3 L1 L3 Va Nb IVc wherein L, W, L3, and R3 are as decribed previously. 2012/076275 In one embodiment, the compound of the invention is according to any one of Formulae Ia-IVc, wherein L1 is absent, or is —O-. In a preferred embodiment, L1 is absent.
In another embodiment, the nd of the ion is according to any one of Formulae Ia- IVc, wherein L1 is -NR4a-, wherein R4&1 is as described previously. In a preferred embodiment, R4&1 is H, Me, Et, or cyclopropyl. In a more preferred embodiment, R4&1 is H.
In one embodiment, the compound of the invention is ing to any one of Formulae Ia-Ic, or IIIa-IVc, wherein W is C14 alkylene. In a preferred ment, W is —CH2-, —CH2-CH2-, —CH2-CH2- CH(CH3)-, —CH2-CH(-CH2-CH3)-, —CH2-C(CH3)2-, or —CH2-CH2-CH2-. In a more preferred embodiment, W is —CH2-. In another more preferred embodiment, W is—CHZ-CH2-.
[0092] In one ment, the compound of the invention is according to any one of Formulae Ia-Ic, or IIIa-IVc, wherein W is C2_4 lene having one double bond. In a preferred embodiment, W is —CH=CH-, —CH2-CH=CH-, or -CH2-. In a more preferred embodiment, W is -CH=CH-. In another more preferred embodiment, W is —CH2-CH=CH-.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or IIIa-IVc, wherein W is C2_4 alkynylene having one triple bond. In a preferred embodiment, W is —CEC-, — CHZ-CEC-, or -CEC-CH2-. In a more preferred embodiment, W is -CEC-. In another more preferred embodiment, W is —CH2-CEC-.
In one embodiment, the compound of the ion is according to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L2 is absent. In another embodiment, L2 is —O-.
[0095] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L1 is absent or is -O-, W is C1_4 alkylene; and L2 and R2 are as described previously. In a preferred embodiment, W is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In a more preferred embodiment, W is — CH2-. In another preferred ment, W is-CHZ-CH2-.
In another embodiment, the compound of the invention is ing to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L1 is absent or is —O-, W is C2_4 alkenylene having one double bond; and L2 and R2 are as described previously. In a preferred embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-. In a more preferred embodiment, W is -CH=CH-. In another more red embodiment, W is -CH2-CH=CH-.
In yet r embodiment, the nd of the invention is according to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L1 is absent, W is C2_4 alkynylene having one triple bond; and L2 and R2 are as described previously. In a preferred embodiment, W is -CEC-, -CH2-CEC-, or -CEC-CH2-. In a more preferred embodiment, W is -CEC-. In another more preferred embodiment, W is -CH2-CEC-.
In one embodiment, the compound of the invention is ing to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L1 and L2 are absent, W is C14 alkylene; and R2 is as described previously. In a preferred embodiment, W is -CH2—, -CH2-CH2-, or -CH2-CH2-CH2-. In a more preferred ment, W is -CH2-. In another more preferred embodiment, W is -CH2-CH2-.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L1 and L2 are absent, W is C2_4 alkenylene having one double bond; and R2 is as described previously. In a red embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH2-. In a more preferred embodiment, W is -CH=CH-. In another more preferred embodiment, W is -CH2-CH=CH-.
In yet another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or IIIa-IIIc, wherein L1 and L2 are absent, W is C2_4 alkynylene having one triple bond; and R2 is as described previously. In a preferred embodiment, W is -CEC-, -CH2-CEC-, or -CEC-CH2-. In a more preferred embodiment, W is -CEC-. In another more preferred embodiment, W is -CH2—CEC-.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is H.
In another ment, the compound of the invention is according to any one of ae any one of Formulae Ia-IIIc, wherein R2 is CH; alkyl. In a preferred embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu. In a more preferred embodiment, R2 is Me, Et, i-Pr or t—Bu. In a more preferred embodiment, R2 is t- In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is C1_g alkyl substituted with one to three groups selected from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three atoms independently selected from N, S, and O), and phenyl. In a red embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t—Bu tuted with one to three groups ed from OH, halo, CN, CM alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In another red embodiment, is C1_g alkyl substituted with one to three groups ed from OH, F, Cl, CN, -OMe, -OEt, Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, ydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a more preferred embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu substituted with one to three groups ed from OH, F, Cl, CN, - OMe, -OEt, -Oz'-Pr, cyclopropyl, utyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, lyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl.
In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, wherein R2 is CH; alkyl substituted with one group selected from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 ed heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In a preferred embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t—Bu substituted with one group selected from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently ed from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms ndently selected from N, S, and O), and phenyl. In r preferred ment, is C1_g alkyl substituted with one group selected from OH, F, Cl, CN, -OMe, -OEt, - Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofiJranyl, tetrahydropyranyl, olyl, imidazolyl, lyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and . In a more preferred embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu substituted with one group selected from OH, F, Cl, CN, -OMe, -OEt, - Oi-Pr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, lyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a most preferred embodiment, R2 is -CH2-OH, -C(CH3)2-OH, -CH(OH)CH3, -CH(OH)—C2H5, -CH(OH)-C3H7, - C(OH)(C2H5)2, -C(OH)H-CH(CH3)2, -C(OH)H-CH2-CH(CH3)2, -C(OH)H-C(CH3)3, -CH2-CN, -CH2-OCH3, - CH2-CH2-OCH3, -CH(OCH3)-CH3, -C(OCH3)H-CH(CH3)2, -CH2-F, —CH2-CH2-F, -CH2-cyclopropyl, -CH2- cyclopentyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, or -CH2-tetrahydropyranyl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is C4_7 cycloalkenyl comprising one double bond. In a preferred embodiment, R2 is cyclohexenyl.
In one embodiment, the nd of the ion is according to any one of ae Ia-IIIc, wherein R2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S. In a preferred embodiment, R2 is dihydropyranyl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is C3_7 cycloalkyl. In a preferred embodiment, R2 is cyclopropyl, cyclobutyl, entyl, or cyclohexyl. In a more preferred embodiment, R2 is cyclopropyl.
In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, wherein R2 is C3_7 cycloalkyl substituted with one to three independently selected R5 groups. In a preferred embodiment, R2 is C34 cycloalkyl substituted with one R5 group. In a more preferred embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group. In another more prefered embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or R6 n R6 is selected from OH, or CM alkyl. In a most prefered embodiment, R2 is cyclopropyl, utyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, n R5 is oxo, or R6 wherein R6 is ed from OH, or C1_6 alkyl. In a further most prefered embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or exyl, each of which is tuted with one R5 group, n R5 is R6, and R6 is selected from OH.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O. In a preferred embodiment, R2 is oxetanyl, ydrofuranyl, tetrahydropyranyl, or dioxanyl. 2012/076275 In another embodiment, the compound of the ion is according to any one of Formulae Ia- IIIc, R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O substituted with one to three independently selected R5 groups. In a red ment, R2 is 4- membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and Osubstituted with one R5 group. In a more preferred embodiment, R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O substituted with one R5 group, wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. In another more red embodiment, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is substituted with one R5 group. In a most red ment, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is substituted with one R5 group, wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl, In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, R2 is 5-10 membered heteroaryl comprising one to three atoms independently selected from N, S, and O. In a preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, azolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
In another embodiment, the nd of the invention is according to any one of Formulae Ia- IIIc, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted substituted with one to three independently selected R6 groups. In a prefered embodiment, R2 is 5-10 membered aryl comprising one to three heteroatoms independently selected from N, S, and O, substituted substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is furanyl, thienyl, oxazolyl, lyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R6 groups. In another more preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two ndently selected R6 groups, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, CM alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered cycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In most preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, CM alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered heterocycloalkyl comprising one to three heteroatoms ndently ed from N, O, and S, and phenyl. In r most preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, tuted with one or two ndently selected R6 groups, wherein each R6 is independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, -CF3, -OMe, -OEt, Oi-Pr, -CN, ropyl, pyrrolidinyl, morpholinyl, WO 92791 piperidinyl, or phenyl. In further most preferred embodiment, R2 is fiJranyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is ndently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t—Bu, -CF3, -OMe, -OEt, -Oz’-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, dinyl, and phenyl.
In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, R2 is C640 aryl. In a preferred embodiment, R2 is phenyl.
In another embodiment, the compound of the invention is according to any one of ae Ia- IIIc, R2 is €6.10 aryl substituted with one or more independently selected R6 groups. In a prefered embodiment, R2 is €6.10 aryl substituted with one or two independently ed R6 . In a more preferred embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, CM alkyl, CM alkoxy, or -NHC(=O)-C1_4 alkyl. In another more preferred embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=O)NR9R1°, and each R9 and R10 is independently selected from from H and C14 alkyl. In yet another more preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups. In a most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, CM alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl. In r most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=O)NR9R1°, and each R9 and R10 is independently selected from from H and C1_4 alkyl. In a further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is ed from F, Cl, CN, Me, -OMe, -OEt, and -NHC(=O)Me. In another further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from - H2, and -C(=O)NHMe.
[00115] In another embodiment, the compound of the invention is according to any one of ae Ia-Ic, IVa, IVb or IVc, wherein L3 is -NR4b-, and R4b is as decribed previously. In a preferred embodiment, R4b is H, Me, Et, or ropyl. In a more preferred embodiment, R4&1 is H.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb or IVc, wherein R3 is C1_4 alkyl substituted with C640 aryl optionally substituted with one or more independently selected R7 groups, or 5-10 membered heteroaryl comprising one to three heteroatoms ndently selected from N, S, and O, ally substituted with one or more R independently selected R7 groups. In a red embodiment, R3 is Me or Et, each of which is tuted with C640 aryl optionally substituted with one or more independently selected R7 ), or 5-10 membered heteroaryl comprising one to three atoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups. In another preferred embodiment, R3 is C1_4 alkyl substituted with phenyl, WO 92791 or pyridyl, each of which is optionally substituted with one or more independently selected R7 groups. In a more preferred embodiment, R3 is C14 alkyl substituted with , or pyridyl. In a more preferred embodiment, R3 is C1_4 alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or Cl. In a most preferred ment, R3 is Me or Et, each of which is substituted with phenyl, or pyridyl.
In a more preferred embodiment, R3 is Me or Et, each of which is substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or Cl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb or IVc, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, s, and o. In a preferred embodiment, R3 is pyridyl.
[00118] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently ed R7 groups, wherein each R7 group is as described previously. In a preferred embodiment, R3 is pyridyl, substituted with one or more independently selected R7 groups, wherein each R7 group is as described usly. In another preferred embodiment, R3 is 5-10 membered heteroaryl sing one to three heteroatoms independently ed from N, S, and O, substituted with one or more independently selected R7 groups, wherein each R7 group is ed from Me, Et, F, and Cl. In a more preferred embodiment, R3 is l substituted with one or more independently selected R7 groups, wherein each R7 group is selected from Me, Et, F, and Cl. In a most preferred embodiment, R3 is pyridyl substituted with one R7 group selected from Me, Et, F, and Cl.
[00119] In one embodiment, the compound of the ion is according to any one of ae Ia-Ic, IVa, IVb, or IVc, wherein R3 is C640 aryl. In a preferred embodiment, R3 is phenyl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R3 is €6.10 aryl substituted with one or more independently selected R7 groups, wherein each R7 group is as described previously. In a preferred embodiment, R3 is , substituted with one or more independently selected R7 groups, wherein each R7 group is as described previously. In another red embodiment, R3 is C640 aryl substituted with one or more independently selected R7 groups, n each R7 group is selected from Me, Et, F, and Cl. In a more preferred embodiment, R3 is phenyl substituted with one or more independently selected R7 groups, wherein each R7 group is ed from Me, Et, F, and Cl. In a most preferred embodiment, R3 is phenyl tuted with one R7 group selected from Me, Et, F, and Cl.
In one embodiment, the compound of the invention is according to Formula Va, Vb, Vc or Vd: 0/} ofi ofi ofi u" Y F’ Y N/ N/ N/ N/ AN I CAN I CAN I CAN I § R2 o/\R2 R2 Va Vb . Vc or Vd wherein R2 is as described previously.
In a further embodiment, the compound of the invention is not according to a Va, Vb, Vc or Vd.
[00123] In another embodiment, the compound of the invention is according to Formula VIa, VIb, VIc or 00. 000 05., co / / o/\R2 R2 Vwherein R2is as described usly. Vlc or Vld In a further embodiment, the compound of the invention is not according to Formula VIa, VIb, VIc or VId.
In another embodiment, the compound of the invention is according to Formula VIIa, VIIb, VIIc or VIId: ofi ofi ofi 3 O O 0 CAN —Z R2 OAR R2 Vlla Vllb VIIC Vlld wherein R2 is as described usly.
[00126] In one embodiment, the compound of the invention is according to Formula Va, Vb, VIa, VIb, VIIa, or VIIb,wherein R2 is C3_7 cycloalkyl. In a preferred embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more red embodiment, R2 is cyclopropyl.
In one ment, the compound of the invention is according to Formula Va, Vb, VIa, VIb, VIIa, or VIIb, wherein R2 is not C3_7 cycloalkyl. In a preferred embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more preferred embodiment, R2 is not cyclopropyl.
In another embodiment, the compound of the invention is according to a Va, Vb, VIa, VIb, VIIa, or VIIb, wherein R2 is C3_7 cycloalkyl substituted with one to three independently ed R5 groups.
In a preferred embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group. In a more preferred ment, R2 is cyclopropyl, utyl, cyclopentyl or cyclohexyl, each of which is tuted with one R5 group. In another more prefered embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or R6 n R6 is selected from OH, or C1_6 alkyl. In a most prefered embodiment, R2 is ropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. In a further most prefered ment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is OH.
In another embodiment, the compound of the ion is according to Formula Va, Vb, VIa, VIb, VIIa, or VIIb, wherein R2 is not C34 cycloalkyl substituted with one to three independently selected R5 groups. In a preferred ment, R2 is not C3_7 cycloalkyl tuted with one R5 group. In a more preferred embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group. In another more prefered embodiment, R2 is not C3_7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and CM alkyl. In a most prefered embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. In a r most prefered embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is OH.
In one embodiment, the compound of the invention is according to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is 5-10 membered aryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, lyl, nyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
In one embodiment, the compound of the invention is ing to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R2 is not furanyl, l, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
In another embodiment, the compound of the invention is according to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one to three independently selected R6 groups. In a prefered embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, tuted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is fiJranyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently ed R6 . In another more preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, CM alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently ed from N, O, and S, and phenyl. In a most preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is tuted with one or two independently selected R6 groups, wherein each R6 is independently ed from OH, halo, C1_6 alkyl, CM alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one to three atoms independently selected from N, O, and S, and . In another most preferred ment, R2 is 5-10 membered aryl comprising one to three heteroatoms independently selected from N, S, and O, tuted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, -CF3, -OMe, -OEt, Oi-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In a r most preferred embodiment, R2 is l, l, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t—Bu, -CF3, -OMe, -OEt, -Oz'-Pr, -CN, cyclopropyl, pyrrolidinyl, linyl, piperidinyl, and phenyl.
In another embodiment, the compound of the invention is according to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one to three independently selected R6 groups. In a prefered embodiment, R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently ed from N, S, and O, substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, lyl, pyridinyl, nyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two ndently selected R6 groups. In another more preferred ment, R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, CM alkyl, C1_6 alkyl substituted with one or more halo, C1_6 alkoxy, -CN, C3_7 cycloalkyl 4-7 membered heterocycloalkyl sing one to three heteroatoms independently selected from N, O, and S, and phenyl.
In a most preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is ndently selected from OH, halo, C1_6 alkyl, C1_6 alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently ed from N, O, and S, and phenyl.
In r most preferred embodiment, R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently ed R6 groups, wherein each R6 is ndently selected from OH, F, Cl, Me, Et, Pr, i-Pr, z-Bu, -CF3, -OMe, -OEt, Oi-Pr, -CN, ropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In a further most preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, olyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, Z-Bu, -CF3, -OMe, -OEt, -Oz'—Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
In another embodiment, the nd of the invention is according to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is C640 aryl. In a preferred embodiment, R2 is phenyl.
] In another embodiment, the compound of the invention is according to Formula Vc, Vd, VIc or VId, wherein R2 is not C640 aryl. In a preferred ment, R2 is not phenyl.
] In another embodiment, the compound of the invention is ing to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is €6.10 aryl substituted with one or more independently selected R6 groups. In a prefered embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, C1_6 alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl. In another more preferred embodiment, R2 is C640 aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=O)NR9R1°, and each R9 and R10 is independently selected from from H and C1_4 alkyl. In another more preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups. In a most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, CM alkyl, CM alkoxy, and O)-C1_4 alkyl. In another most preferred embodiment, R2 is phenyl tuted with one or two independently selected R6 groups, n each R6 group is selected from -C(=O)NR9R1°, and each R9 and R10 is independently selected from from H and C1_4 alkyl. In a further most preferred ment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is ed from F, Cl, CN, Me, -OMe, -OEt, - and -NHC(=O)Me. In a further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from C(=O)NH2, and -C(=O)NHMe.
In another embodiment, the compound of the ion is ing to Formula Vc, Vd, VIc, VId, VIIc or VIId, wherein R2 is not C640 aryl substituted with one or more independently selected R6 groups. In a prefered embodiment, R2 is not €6.10 aryl substituted with one or two independently ed R6 groups. In a more preferred ment, R2 is not €6.10 aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, C1_6 alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl. In another more preferred embodiment, R2 is not C640 aryl substituted with one or two independently selected R6 groups, n each R6 group is selected from -C(=O)NR9R10, and each R9 and R10 is independently ed from from H and C1_4 alkyl. In another more preferred embodiment, R2 is not phenyl substituted with one or two independently ed R6 groups. In a most preferred embodiment, R2 is not phenyl substituted with one or two independently selected R6 groups, n each R6 group is selected from halo, CN, CM alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl, In another most preferred ment, R2 is not phenyl substituted with one or two ndently selected R6 groups, wherein each R6 group is selected from NR9R10, and each R9 and R10 is independently selected from from H and C1_4 alkyl, In a further most preferred embodiment R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from F, Cl, CN, Me, -OMe, -OEt, - and -NHC(=O)Me. In a further most preferred embodiment R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from C(=O)NH2, and -C(=O)NHMe.
In one embodiment, the compound of the invention is selected from: 9 -Allyloxy([1,4]dioxanylmethoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-([1 ,4]Dioxanylmethoxy)-9 -pyridin-3 -yl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-([1 xanylmethoxy)-9 -pyridinyl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-[2-([1,4]Dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-benzonitrile, 3 -[2-([1,4]Dioxanylmethoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-benzonitrile, 4-[2-([1,4]Dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-benzonitrile, [2-([1,4]Dioxan-Z-ylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyloxy]-acetonitrile, 2-([1,4]Dioxanylmethoxy)(oxazolylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-([1 ,4]Dioxanylmethoxy)-9 -(pyridinylmethoxy)—6,7-dihydro-pyrimido[6, 1 -a]isoquinolinone, 9 -(3 ,5 -Dichloro-phenyl)([1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone, 9 -Benzofuranyl([1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone, 2-[2-([1,4]Dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-indolecarboxylic acid tert-butyl ester, 2-([1 ,4]Dioxanylmethoxy)-9 -(1H-indolyl)-6,7 -dihydro-pyrimido[6,1 -a]isoquinolinone, 2-([1 ,4]Dioxanylmethoxy)-9 -(6-methoxy-pyridin-3 -yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-([1,4]Dioxanylmethoxy)(6-trifluoromethyl-pyridinyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one, 2-([1 ,4]Dioxanylmethoxy)-9 -(3 -methyl-3H-imidazolylethynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 9 -(5 -tert-Buty1— [1 ,2 ,4]oxadiazol-3 -y11nethoxy)([1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, -[2-([1,4]Dioxany1methoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]-pyridine carboxylic acid methylamide, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -pentyny1-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2-([1 4,]Dioxany1methoxy)(2-pyridiny1-ethy1)-6,7 ro-pyrimido[6, 1 a—]isoquinolinone, 2-([1,4]Dioxany1methoxy)(2--pyrazin-y1-ethy1)-6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone, 2-([1,4]Dioxany1methoxy)(1H-indol-5 --y1)6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone, 2-([1,4]Dioxany1methoxy)(2-methoxy-pheny1)-6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone, 2-([1,4]Dioxany1methoxy)(5 m—e-thoxypyridiny1)-6,7-dihydro-pyrimido[6, 1 a—]isoquinolinone, 2-([1,4]Dioxany1methoxy)(1H-indazol—5 -yl)-6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone, 4]Dioxany1methoxy) 9 (4 methoxy pheny1)-6 7 dihydro pyrimido[6 1 a]isoquinolin 4 one 3- [2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]-benzamide, - [2-([1 4,]Dioxany1methoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]fluoro- benzamide, N— {3 -[2-([1,4]Dioxany1methoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]-pheny1}- acetamide, 9 -Cyclopropy1ethyny1—2-( [1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(1 -hydroxy-cyclopentylethynyl) -6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin-4 - one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -pyrimidin-5 -y1-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 9 -Cyclohexeny1([1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2 -( [1 ,4 ny1methoxy)-9 -(1-methy1—1H-indol-5 -y1)-6,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 2 -( [1 ,4 ny1methoxy)-9 -(6-methy1—pyridin-3 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -pyridiny1ethyny1-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ny1methoxy)-9 -(3 -methoxy-propyny1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -pentynenitrile, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-propyny1)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(4-methoxy-pheny1ethyny1)-6 ,7 -dihydro-pyrimido [6 ,1 quinolinone, 2 -( [1 ,4 ny1methoxy)-9 -pyridin-3 -y1ethyny1-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 4-[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -N-methy1— benzamide, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 xy-pheny1)-6,7 -dihydro-pyrimido [6, 1 -a]isoquinolinone, 9 -(2-Chloro-pheny1)([1,4]dioxany11nethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(4-hydroxy-but-1 -yny1)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone, 9 -(1,5 -Dimethy1—1H-pyrazol—3 -y1methoxy)([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(1-methy1—1H-pyrazol-3 thoxy)—6,7 -dihydro-pyrimido[6,1- a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -methy1—[1,2,4]oxadiazol-5 -y1methoxy)-6,7-dihydro-pyrimido[6,1- uinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(4-morpholiny1-pheny1)—6,7-dihydro-pyrimido [6, 1 -a]isoquinolinone, 3 -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido [6, 1 -a] isoquinolin-9 -y1] fluoro- benzamide, 3 -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -5 -fluoro- ide, 9 -(3 ,3 -Dimethy1—butyny1)([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -pyridiny1ethyny1—6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -methy1—isoxazol-5 -y1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-3 -methy1—but6,7-dihydro-pyrimido [6, 1 -a] isoquinolin one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-methoxy-pyridin-3 -y1)-6,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 9 -(3 ,6-Dihydro-2H-pyran-4 -y1)([1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -pyridine carbonitrile, 2 -( [1 ,4 ]Dioxany1methoxy)-9 opropoxy-pyridin-3 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(6-ethoxy-pyridin-3 -y1)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(6-morpholiny1-pyridin-3 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin one, 9 -(2,3 -Dimethoxy—pheny1)([1,4]dioxany11nethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 9 -(3 -Chloromethoxy-pyridiny1)([1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-methy1—pyridin-4 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 3 -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -isonicotinonitri1e, 9 -(2,5 -Dimethoxy—pheny1)([1,4]dioxany11nethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2-([1,4]Dioxany1methoxy)-9 -(3 ,4,5 rahydro-2H- [1 ,2']bipyridiny1—5 6 ydro-pyrimido [6 ,1 - a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-ethoxy-pyridin-3 -y1)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 9 -(2,6-Dimethoxy—pyridin-3 -y1)-2 -( [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 4-[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -nicotinonitri1e, 9 -tert-Butoxymethy1—2-([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-pyrrolidiny1-pyridin-3 -y1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(6-pyrrolidiny1-pyridin-3 -y1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -pheny1-oxazoly1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolin one, 9 -(5 Buty1—oxazol—2-y1methoxy)—2-([1,4]dioxany11nethoxy)-6 ,7 ro-pyrimido [6 ,1 -a]isoquinolin-4 - one, 9 -(5 -Cyclopropy1—[1,2,4]oxadiazol-3 -y1methoxy)([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -ethy1-[1,2,4]oxadiazol-3 -y1methoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -methy1—[1,2,4]oxadiazol-3 -y1methoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -isopropy1— [ 1 ,2,4] oxadiaz01-3 -y1methoxy)-6 ,7 ro-pyrimido [6 ,1 - a]isoquinolinone, 9 pentylethyny1( [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 9 -Cyclohexy1ethyny1—2 -([1 xany1methoxy)—6,7-dihydro-pyrimido [6, 1 -a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -methy1—butyny1)-6,7 ro-pyrimido [6,1 -a]isoquinolinone, 2 -( [1 ,4 ny1methoxy)-9 -hexyny1-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 9 - [3 -(B enzyl-methyl-amino)-prop-1 -yny1] -2 -( [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 - a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-5 -methy1—hex-1 -yny1) -6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolin one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-but-1 -yny1)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone, 9 -Cyclopropy1—2-([1,4]dioxany11nethoxy)—6,7 -dihydro-pyrimido[6,1-a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-pentyny1)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxymethy1—pentyny1)-6,7 ro-pyrimido [6,1 -a]isoquinolin- 4-one, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -ethy1-3 -hydroxy—pentyny1)-6,7-dihydro-pyrimido [6, 1 -a]isoquinolin-4 - one, WO 92791 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-3 -pheny1—butyny1)-6,7-dihydr0-pyrimid0 [6, 1 -a] is0quin01in one, 9 -(3 -Benzylamino-prop -1 -yny1) -2 -( [1 ,4]di0xany1meth0xy)-6,7-dihydr0-pyrimid0 [6, 1 -a] n01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -[(fiirany1methy1)-amin0] -6 ,7-dihydr0-pyrimid0 [6 ,1 -a] n01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(1 -ethy1— 1 H-pyraz01y1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in-4 -0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -[1-(3 -methy1-buty1)-1H-pyraz01-4 -y1] -6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(5 -methyl-furany1) -6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-hex-1 -yny1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne, 9 -(3 ,5 -Dimethy1— 1 z01y1)( [1 xany1meth0xy)-6 ,7-dihydr0-pyrimid0 [6 1 -a] is0quin01in one, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(1H-pyraz01—4-y1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(1-pr0py1—1H-pyraz01—4 -y1)-6,7-dihydr0-pyrimid0 [6, 1 -a] is0quin01in0ne, 2 - [2-((R)-1 -[1,4]Dioxany1meth0xy)—4-0X0-6,7-dihydr0-4H-pyrimid0 [6, 1 -a] is0quin01in-9 -y1] -benzonitrile, 2-[2-((S)[1,4]Dioxany1meth0xy)—4-0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quin01iny1]-benz0nitrile, 9 -(5 -Cyclopr0py1—[1,2,4]0xadiaz01—3 -y1meth0xy)—2-((R)[1,4]di0xany1meth0xy)-6 ,7 -dihydr0- pyrimido [6 ,1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -ethyny1—6 ,7 -dihydr0-pyrimid0 [6 ,1 quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 idinylethyny1-6,7-dihydr0-pyrimid0 [6, 1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -pheny1amin0-pr0p-1 -yny1)-6 ,7-dihydr0-pyrimid0 [6 ,1 -a] is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-3 -pyridin-3 -y1-pr0p -1 -yny1) -6 ,7 r0-pyrimid0 [6 ,1 - a]is0quin01in0ne, 9 -Cyclopentyloxymethyl([1 ,4]dioxany1meth0xy)—6,7-dihydr0-pyrimid0 [6, 1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -meth0xymethy1—p entyny1)-6,7-dihydr0-pyrimid0 [6, 1 quin01in- 4-0ne, 9 -Cyclopr0pylethyny1((R)[1,4]di0xany1meth0xy)-6 ,7 -dihydr0-pyrimid0 [6 ,1 quin01in0ne, 2-((S) [1 ,4]Di0xany1meth0xy)-9 -(3 1-but-1 -yny1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -imidaz01-1 -y1-pr0p -1 -yny1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in-4 - one, 9 -(2-Cyclopropyl-ethy1)((R)[1,4]di0xany1meth0xy)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne, 9 -Cyclopentyloxymethyl((R)-1 -[1 ,4]dioxany1meth0xy)—6,7-dihydr0-pyrimid0 [6, 1 -a]is0quin01in0ne, 2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-3 -pyridin-3 -y1-pr0py1)—6,7 -dihydr0-pyrimid0 [6, 1 -a]is0quin01in- 4-0ne, 9 -A11y10xy((R)[1,4]dioxany1meth0xy)-6,7-dihydr0-pyrimid0[6,1-a]is0quin01in0ne, 9 -A11y10xy((S)[1,4]dioxany1meth0xy)—6,7-dihydr0-pyrimid0[6,1-a]is0quin01in0ne, 2-((R) [1 ,4 ]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyranyloxymethy1) -6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 - {3 - [(pyridin-3 -y1methy1)—amino]-prop -1 -yny1} -6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone, 2-((R) [1 ,4 ]Dioxan-2 -y11nethoxy)-9 -p enty1-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 9 propy1ethyny1—2-((S) [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 9 clopropy1—ethy1)((S)[1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(oxetan-3 -yloxymethy1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -methy1-oxetan—3 -y1methoxymethy1)—6,7 -dihydro-pyrimido[6,1- a]isoquinolinone, 9 -(2,2-Dimethy1—buty1amino)((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—4-methy1-penty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(2-ethy1-hexy1amino)-6,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 thoxy-ethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(2-ethoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 quinolinone, 9 -Cyclopropy1methoxy((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-((S) [1 xan-2 -y11nethoxy)-9 -(2-fluoro-ethoxy)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 - [3 -(2-methoxy—ethoxy)—propyny1]-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone, 2-((S)[1,4]Dioxany11nethoxy)-9 -[3 -(2-ethoxy—ethoxy)-propyny1]-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 2-((S)[1,4]Dioxany11nethoxy)-9 -[3 oro-ethoxy)-propyny1]-6,7 ro-pyrimido[6,1- a]isoquinolinone, 9 -(2,2-Dimethy1—propoxymethy1)((S)-1 -[1,4]dioxany1methoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 9 -Cyclohexyloxymethy1((S) [1 ,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 9 -Cyclopropylmethoxymethyl—2-((S) [1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] nolin one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyrany1methoxy)-6 ,7 ro-pyrimido [6 ,1 - a]isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—buty1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin-4 -one, 9 -(4,4-Dimethy1—pentyloxy)((S)— 1 - [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin one, [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -methoxymethy1—penty1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin- 4-one, 9 -(3 -Cyclopropy1—propoxy)((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin one, 9 hexy1amino((S)— 1 - [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—4,4-dimethy1—penty1)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 9 -Cyclopentylmethoxymethy1((S) [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin one, [1 xan-2 -y11nethoxy)-9 -(3 -methoxy-buty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -pheny1amino-propy1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin-4 - one, 2-((S) [1 ,4]Dioxan-2 thoxy)-9 -(4-hydroxy—p enty1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(4-hydroxy—buty1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone, 9 -(Cyclohexyl-methyl-amino)((S) [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] nolin one, 9 -(Cyclohexylmethyl-amino)((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin-4 - one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 - [(tetrahydro-pyrany1methy1)-amino] -6,7-dihydro-pyrimido[6,1- a]isoquinolinone, 2-((S) [1 ,4]Dioxan-2 thoxy)-9 -(3 -ethy1-3 -hydroxy—penty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—3 -methy1-buty1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—p enty1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 9 -(2,2-Dimethy1—propoxy)((S) [1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyrany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone, 2-((S) [1 ,4]Dioxan-2 thoxy)-9 -(4-hydroxy—4-methy1-penty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyrany1methoxymethy1)—6,7-dihydro-pyrimido [6, 1 - a]isoquinolinone, 2 -( [1 ,4 ]Dioxany1methoxy)-9 -methoxy—6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone, 2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(oxetan-3 -y1methoxy)-6 ,7 ro-pyrimido [6 ,1 -a]isoquinolin-4 -one, 2012/076275 9 -(3 -Cyclopropyl-propoxy)((R)[1 ,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one, 2-((S)[1 ,4]Dioxanylmethoxy)-9 -(3 -methoxy-propyl)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone, [1 ,4]Dioxanylmethoxy)-9 -[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7 -dihydro-pyrimido [6,1 - uinolinone, 2-((R)[1 ,4]Dioxanylmethoxy)-9 -(4-hydroxy-tetrahydro-pyranylethynyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone, In one embodiment, the compound of the invention is selected from: [1 ,4]Dioxanylmethoxy)-9 -(3 -methoxy-propyl)-6,7 -dihydro-pyrimido [6,1 quinolinone, 2-((R)[1 ,4]Dioxanylmethoxy)-9 -[2-(1 -hydroxy-cyclopentyl)-ethyl] -6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone, 2-((S)[1 ,4]Dioxanylmethoxy)-9 -(2-propoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone, 2-((S)[1 ,4]Dioxanylmethoxy)-9 opropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-((R)[1,4]Dioxanylmethoxy)(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, [1 ,4]Dioxanylmethoxy)-9 -(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone, 2-((S)[1 ,4]Dioxanylmethoxy)-9 -(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
In one embodiment, the compound of the invention is 9-cyclopropylethynyl((S)[1,4]dioxan- 2-ylmethoxy)-6,7 -dihydro-pyrimido[6,1 -a]isoquinolinone.
[00141] In another embodiment, the compound of the invention is not opropylethynyl((S) [1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
] In one embodiment a compound of the invention is not an isotopic variant.
In one aspect a compound of the invention is present as the free base.
] In one aspect a compound of the invention is a pharmaceutically acceptable salt.
[00145] In one aspect a compound of the invention is present as the free base or a pharmaceutically acceptable salt.
In one aspect a compound of the invention is a solvate.
In one aspect a compound of the invention is a solvate of a ceutically acceptable salt of the compound.
[00148] In certain aspects, the t invention provides prodrugs and derivatives of a compound of the invention according to the formula above. Prodrugs are derivatives of a compound of the invention, Which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N—alkylmorpholine esters and the like.
] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian sm (see, Bundgard, H. Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to tioners of the art, such as, for e, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or ic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is ble to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C1 to C3 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
While specified groups for each embodiment have generally been listed above tely, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. ore, this invention is intended to include all combinations of such embodiments within its scope.
While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is ed from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed ments within its scope.
Alternatively, the exclusion of one or more ofthe specified variables from a group or an embodiment, or combinations thereof is also contemplated by the t ion.
CLAUSES 1. A compound according to Formula la: WO 92791 wherein R1 is H, Me, or halo; L1 is absent or is —O-, -S-, or -NR4a-; G is -W-L2-R2, or -W-L3-R3; W is C1_4 alkylene, C2_4 lene having one double bond, or C2_4 alkynylene having one triple bond; L2 is absent or is —O-; R2 is _ H, - C1_g alkyl, optionally substituted with one to three groups independently selected from O OH, O halo, O CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl comprising one to three heteroatoms ndently selected from S, and 0, -6 membered heteroaryl comprising one to three atoms independently selected from N, S, and O, and O phenyl, - C4_7 cycloalkenyl comprising one double bond, - 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S, - C3_7 cycloalkyl optionally substituted With one or more independently selected R5 groups, - 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 groups, - 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O optionally substituted with one to three independently ed R6 groups, or - C640 aryl optionally substituted with one or more independently ed R6 groups; L3 is -NR4b-; R3 is - C1_4 alkyl substituted With 0 C640 aryl optionally substituted with one or more independently selected R7 groups, or 0 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups, -10 ed heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted With one or more independently selected R7 group, or - €6.10 aryl ally substituted with one or more independently selected R7 groups; Each R4&1 and R4b is independently selected from H, C14 alkyl, and C3_7 lkyl; R5 is oxo or R6; R6 is - OH, - halo, - -NOZ, - C1_6 alkyl optionally substituted With one to three groups independently selected from halo, and - C1_6 alkoxy optionally substituted With one to three groups ndently selected from halo, and OH, - C3_7 cycloalkyl, - -C(=O)OR8, - -C(=O)NR9R1°, - -NHC(=O)-C1_4 alkyl, - -CN, - phenyl, - -O-phenyl, - 4-7 membered heterocycloalkyl comprising one to three heteroatoms ndently selected from N, O, and S, or - 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S, optionally substituted with one or more indepentently selected C14 alkyl, C1_4 alkoxy, CN, halo), and -C(=O)OR“; R7 is C1_4 alkyl, or halo; and each of R8, R9, R10 and R11 is independently selected from H and C1_4 alkyl, or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable salt. 2. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the nd is according to Formula lb: lb wherein R1, L1 and G are as usly bed. 3. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the nd is according to Formula Ic: wherein R1, L1 and G are as previously described.
A compound or pharmaceutically acceptable salt thereof, according to any one of s 1-3, wherein R1 is Me, F, or Cl.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-3, wherein R1 is H.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, wherein the compound is according to Formula Ila, Ilb or Hc: ofi o ofi L1—R2 L1—R2 L1—R2 Ila Ilb ||c wherein L1, and R2 are as described in claim 1.
A compound or pharmaceutically acceptable salt f, according to clause 1 or 2, wherein the compound is according to Formula Illa, Illb, or IIIc: ofi ofi ofi aO 2O r O O o I N’ N/ I I I o N CAN 0 N /W\ /R2 /W\ /R2 L1 L2 L1 L2 L1/W\L/ R22 Illa |||b IIIc n L, W, L2, and R2 are as decribed previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, n the compound is according to Formula IVa, lVb, or IVc: ofi o ofi W\ R3 W\ R3 W\ R3 LT Lg L7 Lg L1 L3 IVa IVb IVC wherein L, W, L3, and R3 are as described in claim 1.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein L1 is absent.
. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein L1 is—O-. 11. A nd or ceutically acceptable salt thereof, according to any one of clauses 1-8, wherein L1 is -NR4a-, and R4&1 is H, Me, Et, or cyclopropyl. 12. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein L1 is -NR4a-, and R4a is H. 13. A compound or pharmaceutically able salt thereof, according to any one of clauses 1-5, or 7-11, wherein W is C1_4 alkylene. 14. A compound or pharmaceutically acceptable salt thereof, according to clause 13, n W is —CH2-, —CH2-CH2-, —CH2-CH2-CH(CH3)-, —CH2-CH(-CH2-CH3)-, —CH2-C(CH3)2-, or —CH2-CH2-CH2-.
. A compound or pharmaceutically acceptable salt thereof, ing to clause 14, wherein W is —CH2- CH2-. 16. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11, wherein W is C2_4 alkenylene having one double bond. 17. A compound or pharmaceutically able salt thereof, according to clause 16, wherein W is — CH=CH-, —CH2-CH=CH-, or -CH=CH-CH2. 18. A compound or pharmaceutically acceptable salt thereof, according to clause 17, wherein W is - CH=CH-. 19. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11, wherein W is C2_4 alkynylene haVing one triple bond.
. A compound or pharmaceutically acceptable salt thereof, according to clause 19, wherein W is —CEC-, —CH2-CEC-, or H2-. 21. A compound or pharmaceutically able salt thereof, according to clause 20, wherein W is -CEC-. 22. A compound or pharmaceutically able salt thereof, according to any one of clauses 1-5, 7, or 9- 21, wherein L2 is —O-. 23. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, 7, or 9- 21, wherein L2 is absent. 24. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, 7, or 9- 21, wherein L1 and L2 are absent, and W is -CH2-, H2-, or H2-CH2-.
. A compound or pharmaceutically able salt thereof, according to clause 1-5, 7, or 9-21, wherein L1 and L2 are absent, and W is -CH=CH-, -CH2-CH=CH-, or -CH2-. 26. A compound or pharmaceutically acceptable salt thereof, according to clause 1-5, 7, or 9-21, wherein L1 and L2 are absent, and W is -CEC-, -CH2-CEC-, or -CEC-CH2-. 27. A nd or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, wherein R2 is H. 28. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, n R2 is CH; alkyl. 29. A compound or ceutically acceptable salt thereof, according to clause 28, wherein R2 is Me, Et, n-Pr, i-Pr, i-Bu, or l—Bu.
. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, n R2 is CH; alkyl substituted with one group selected from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and . 31. A compound or pharmaceutically able salt thereof, ing to any one of clauses 1-7, or 9-25, wherein R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t—Bu, each of which is substituted with one group selected from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 ed heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. 32. A compound or pharmaceutically acceptable salt f, according to any one of clause 30, wherein R2 is C1_g alkyl substituted with one group selected from OH, F, Cl, CN, -OMe, -OEt, -Oz'-Pr, cyclopropyl, utyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and . 33. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, n R2 is C4_7 cycloalkenyl comprising one double bond. 34. A compound or pharmaceutically able salt thereof, according to clause 33, wherein R2 is cyclohexenyl. 35. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, wherein R2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S. 36. A compound or pharmaceutically acceptable salt thereof, according to clause 35, wherein R2 is dihydropyranyl. 37. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, n R2 is C3_7 cycloalkyl. 38. A compound or pharmaceutically acceptable salt f, according to any one of clauses 1-7, or 9-25, wherein R2 is C3_7 cycloalkyl substituted with one R5 group. 39. A compound or pharmaceutically acceptable salt thereof, according to clause 38, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and CM alkyl. 40. A compound or pharmaceutically acceptable salt thereof, according to clauses 37, 38 or 39, wherein R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 41. A nd or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, wherein R2 is 4-10 membered cycloalkyl comprising one to two heteroatoms independently selected from S, and O. 42. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, substituted with one R5 group. 43. A compound or pharmaceutically acceptable salt thereof, according to clause 42, wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. 44. A compound or pharmaceutically acceptable salt thereof, according to clause 41, 42 or 43, wherein R2 is yl, tetrahydrofuranyl, ydropyranyl, or yl. 45. A compound or pharmaceutically acceptable salt thereof, according to any one of s 1-7, or 9-25, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. 46. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups. 47. A compound or pharmaceutically acceptable salt thereof, according to clause 46, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, C1_6 alkyl substituted with one or more halo, C1_6 alkoxy, -CN, C3_7 lkyl 4-7 membered cycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. 48. A compound or pharmaceutically acceptable salt thereof, according to clause 45, 46 or 47, wherein R2 is l, thienyl, oxazolyl, thiazolyl, zolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl. 49. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25, n R2 is C640 aryl. 50. A compound or pharmaceutically acceptable salt thereof, according to any one of s 1-7, or 9-25, wherein R2 is €6.10 aryl, tuted with one or two independently selected R6 groups. 51. A compound or pharmaceutically acceptable salt f, according to clause 50, wherein R6 is selected from halo, CN, CM alkyl, CM alkoxy, -NHC(=O)-C1_4 alkyl, and -C(=O)NR9R1°, wherein each R9 and R10 is ndently selected from from H and C1_4 alkyl. 52. A compound or pharmaceutically acceptable salt thereof, ing to clause 49, 50 or 51, wherein R2 is phenyl. 53. A compound or pharmaceutically acceptable salt f, according to any one of clauses 1-5, or 8-21, wherein L3 is -NR4b-, and R4b is H, Me, Et, or cyclopropyl. 54. A compound or pharmaceutically able salt thereof, according to any one of clauses 1-5, or 8-21, wherein R3 is C1_4 alkyl substituted with phenyl, or pyridyl. 55. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21, wherein R3 is C1_4 alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or Cl 56. A nd or pharmaceutically acceptable salt f, according to any one of s 1-5, or 8-21, wherein R3 is 5-10 membered heteroaryl sing one to three heteroatoms independently selected from N, S, and O. 57. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R7 groups. 58. A compound or pharmaceutically acceptable salt f, according to clause 57 wherein R7 is selected from Me, Et, F, and Cl. 59. A compound or ceutically acceptable salt thereof, according to clause 56, 57, or 58 wherein R3 is pyridyl. 60. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21, n R3 is C640 aryl. 61. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21, wherein R3 is C640 aryl, substituted with one or more independently selected R7 groups. 62. A compound or pharmaceutically acceptable salt thereof, ing to clause 61, wherein R7 is selected from Me, Et, F, and Cl. 63. A compound or pharmaceutically acceptable salt f, according to clause 60, 61, or 62, wherein R3 is phenyl. 64. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Va: wherein R2 is as bed previously. 65. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vb: wherein R2 is as described previously. 66. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vc: o R2 n R2 is as described previously. 67. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is ing to Formula Vd: wherein R2 is as described previously. 68. A compound or pharmaceutically acceptable salt thereof, ing to clause 1, wherein the compound is ing to Formula Vla: wherein R2 is as described previously. 69. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vlb: wherein R2 is as described preViously. 70. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vlc: wherein R2 is as bed preViously. 71. A compound or pharmaceutically acceptable salt f, according to clause 1, wherein the nd is according to Formula Vld: wherein R2 is as described previously. 72. A nd or pharmaceutically acceptable salt thereof, according to clause 1, wherein the nd is according to Formula Vlla: Vlla wherein R2 is as described preViously. 73. A nd or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vllb: Vllb wherein R2 is as described preViously. 74. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIIc: o N OARZ VIIC n R2 is as described previously. 75. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vlld: Vlld wherein R2 is as described preViously. 76. A compound or pharmaceutically acceptable salt thereof, according to clause 64, 65, 68, 69, 72, or 73, n R2 is C3_7 cycloalkyl. 77. A compound or pharmaceutically acceptable salt thereof, according to clause 64, 65, 68, 69, 72, or 73, n R2 is C3_7 cycloalkyl substituted with one R5 group. 78. A compound or pharmaceutically acceptable salt thereof, according to clause 77, wherein R5 is oxo, or R6 wherein R6 is OH, or C1_6 alkyl. 79. A compound or pharmaceutically acceptable salt thereof, according to clause 76, 77 or 78, wherein R2 is cyclopropyl, utyl, cyclopentyl or cyclohexyl. 80. A compound or pharmaceutically able salt thereof, according to clause 66, 67, 70, 71, 74, or 75, wherein R2 is 5-10 ed heteroaryl comprising one to three atoms independently selected from N, S, and O. 81. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71, 74, or 75, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups. 82. A compound or pharmaceutically acceptable salt thereof, according to clause 81, wherein R6 is selected from OH, halo, CM alkyl, C1_6 alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 WO 92791 cycloalkyl 4-7 membered sing one to three heteroatoms , heterocycloalkyl independently selected from N, O, and S, and phenyl. 83. A compound or pharmaceutically acceptable salt thereof, ing to clause 80, 81 or 82, wherein R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl. 84. A compound or pharmaceutically acceptable salt f, according to clause 66, 67, 70, 71, 74, or 75, wherein R2 is C640 aryl. 85. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71, 74, or 75, wherein R2 is C640 aryl substituted with one or two independently selected R6 groups. 86. A compound or pharmaceutically acceptable salt thereof, according to clause 85, n R6 is selected from halo, CN, C1_6 alkyl, C1_6 alkoxy, -NHC(=O)-C1_4 alkyl, and -C(=O)NR9R10, and each R9 and R10 is independently selected from from H and C1_4 alkyl. 87. A compound or pharmaceutically acceptable salt thereof, according to clause 84, 85 or 86, wherein R2 is phenyl. 88. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is 9-cyclopropylethynyl((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -a]isoquinolin one. 89. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is not 9-cyclopropylethynyl((S)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
PHARMACEUTICAL COMPOSITIONS When employed as a pharmaceutical, a compound of the invention is typically stered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the ceutical art and comprise at least one active compound. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of a compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, ing the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the t’s symptoms, and the like.
The ceutical compositions of the invention can be administered by a y of routes including oral, , transdermal, subcutaneous, intra-articular, enous, intramuscular, intranasal and tion. Depending on the intended route of delivery, a compound of this invention is preferably formulated as either able or oral compositions or as salves, as lotions or as patches all for transdermal administration.
The itions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the itions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic , in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, a compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing , colorants, flavors and the like. Solid forms may include, for example, any of the ing ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum anth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[00157] Injectable compositions are lly based upon injectable e saline or ate-buffered saline or other inj ectable carriers known in the art. As before, the active compound in such compositions is lly a minor component, often being from about 0.05 to 10% by weight with the remainder being the inj ectable carrier and the like. ermal compositions are typically formulated as a topical ointment or cream containing the active ient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more ably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include onal ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this ion.
] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
] The above-described components for orally administrable, inj ectable or topically administrable compositions are merely representative. Other materials as well as sing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack hing Company, , Pennsylvania, which is incorporated herein by reference.
A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of entative sustained release materials can be found in Remington’s Pharmaceutical es.
The following formulation examples illustrate representative ceutical compositions that may be prepared in accordance with this invention. The present ion, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
Formulation 2 - Capsules A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
Formulation 3 - Liquid ] A compound of the invention (125 mg), may be d with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring.
Sufficient water may then be added with stirring. Sufficient water may be then added to produce a total volume of 5 mL.
Formulation 4 - Tablets A compound of the invention may be admixed as a dry powder with a dry n binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture is formed into 0 mg s (150-300 mg of active amide compound) in a tablet press.
Formulation 5 - Injection A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6 - Topical Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting e may be stirred until it congeals.
METHODS OF ENT A compound of the invention may be used as a therapeutic agent for the treatment of conditions in mammals that are causally related or attributable to aberrant ty of GPR84 and/or aberrant GPR84 sion and/or aberrant GPR84 distribution.
Accordingly, a compound and pharmaceutical compositions of the invention find use as therapeutics for the prophylaxis and/or treatment of inflammatory conditions (e.g. atory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial es (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, ious diseases, autoimmune diseases, endocrine and/or lic diseases, and/or diseases involving impairment of immune cell fimctions, in mammals including humans.
Accordingly, in one aspect, the t invention provides the compound of the invention, or a pharmaceutical ition comprising the compound of the invention for use as a medicament.
] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament.
In yet another aspect, the present invention provides a method of treating a mammal having, or at risk of having a disease disclosed herein. In a particular aspect, the present invention provides a method of treating a mammal having, or at risk of having atory ions (e.g. inflammatory bowel es (IBD), rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e. g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell fimctions, in mammals including humans.
[00174] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a ne for the prophylaxis and/or treatment of inflammatory conditions. In a specific embodiment, the inflammatory condition is selected from atory bowel disease (IBD), rheumatoid arthritis, itis, chronic obstructive pulmonary disease , and idiopathic pulmonary fibrosis (IPF).
In another aspect, the present invention provides the compound ofthe invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of inflammatory conditions. In a specific embodiment, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic ctive ary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with inflammatory conditions, which method comprises administering an ive amount of a compound of the ion, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
In another aspect, the present ion es a method of treating a mammal having, or at risk of having a disease selected from inflammatory conditions (for e inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e. g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune es, endocrine and/or metabolic es, and/or diseases involving impairment of immune cell fiJnctions.
In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition sing the nd of the invention for use as a medicine for the prophylaxis and/or treatment of nflammatory conditions, Guillain-Barré syndrome (GB S), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
In r aspect, the present invention provides the compound ofthe invention, or a pharmaceutical composition comprising the compound of the invention for use in the cture of a medicament for the prophylaxis and/or treatment of neuroinflammatory conditions, Guillain-Barré syndrome (GB S), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
In additional method of ent aspects, this invention provides methods of ent and/or prophylaxis of a mammal susceptible to or afflicted with neuroinflammatory conditions, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
] In one aspect, the present invention provides the compound of the ion, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or ent of ious e. In a specific embodiment, the infectious diseases is selected from sepsis, septicemia, endotoxemia, ic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, ella, Chlamydia, Shigella, enterobacteria species.
In another aspect, the present invention provides the compound ofthe invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a ment for the prophylaxis and/or treatment of infectious disease. In a specific embodiment, the infectious diseases is selected from , septicemia, endotoxemia, systemic inflammatory se syndrome (SIRS), gastritis, enteritis, colitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
In additional method of ent aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with infectious disease, which method ses administering an effective amount of a nd of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other ions involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of autoimmune diseases, and/or diseases involving impairment of immune cell functions. In a specific embodiment, the autoimmune diseases and/or diseases involving impairment of immune cell functions is ed from COPD, asthma, psoriasis, systemic lupus erythematosis, type I es mellitus, vasculitis and inflammatory bowel disease.
In another aspect, the present invention provides the nd ofthe invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of autoimmune es and/or diseases involving impairment of immune cell ons. In a specific ment, the autoimmune diseases, and/or diseases ing impairment of immune cell fiJnctions is selected from COPD, asthma, psoriasis, systemic lupus matosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with autoimmune diseases and/or diseases involving impairment of immune cell functions, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the autoimmune diseases and/or diseases involving ment of immune cell ons is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, itis and inflammatory bowel disease. 2012/076275 In one aspect, the present invention provides the compound of the invention, or a pharmaceutical ition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of endocrine and/or metabolic diseases. In a specific embodiment, the endocrine and/or metabolic diseases is selected from hypothyroidism, ital l hyperplasia, diseases of the parathyroid gland, diabetes mellitus, es of the adrenal glands (including Cushing’s syndrome and Addison’s disease), ovarian dysfunction (including stic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of endocrine and/or metabolic diseases. In a specific ment, the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the l glands (including g’s syndrome and Addison’s disease), ovarian ction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[00189] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with endocrine and/or metabolic diseases, Which method comprises stering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the endocrine and/or metabolic diseases is ed from hypothyroidism, congenital l hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing’s syndrome and Addison’s disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
As a further aspect of the invention there is ed a nd of the invention for use as a medicament especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
A particular regimen of the present method comprises the administration to a subject in ing from an inflammatory condition, of an effective amount of a nd of the ion for a period of time sufficient to reduce the level of inflammation in the subject, and preferably terminate, the processes responsible for said inflammation. A special ment of the method comprises administering of an effective amount of a compound of the invention to a subject suffering from or susceptible to the development of inflammatory condition for a period of time sufficient to reduce or prevent, respectively, inflammation of said patient, and preferably ate, the ses responsible for said inflammation.
Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or 2012/076275 more may also be administered to achieve te steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for ping the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for ping a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[00195] A compound of the ion can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side s seen.
[00196] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of an atory condition; particular agents include, but are not limited to, immunoregulatory agents e.g. oprine, corticosteroids (e. g. solone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g.
Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and cam.
[00197] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e. g. rheumatoid arthritis); ular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for e but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin), and biological DMARDS (for example but without limitation Infliximab, Etanercept, Adalimumab, Rituximab, mab, Certolizumab pegol, Tocilizumab, Interleukin 1 blockers and Abatacept).
In one embodiment, a nd of the invention is co-administered with another therapeutic agent for the treatment and/or tion of autoimmune diseases; particular agents include but are not limited to: glucocorticoids, cytostatic agents (e. g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), tabolites (e.g. methotrexate, azathioprine and topurine), cytotoxic antibiotics (e. g. dactinomycin anthracyclines, cin C, bleomycin, and mithramycin), antibodies(e.g., anti-CD20, anti-CD25 or D3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g.
IFN—B), TNF binding proteins (e.g. infliximab (RemicadeTM), cept (EnbrelTM), or adalimumab (HumiraTM)), mycophenolate, Fingolimod, and Myriocin.
In one embodiment, a compound of the invention is inistered with another therapeutic agent for the treatment and/or prevention of infectious diseases; particular agents include but are not limited to antibiotics. In a particular embodiment, a compound of the invention is co-administered With another therapeutic agent for the treatment and/or prevention of infections of any organ of the human body; particular agents include but are not limited to: aminoglycosides, ansamycins, carbacephem, carbapenems, cephalosporins, glycopeptides, amides, macrolides, monobactams, nitrofurans, penicillins, ptides, quinolones, sulfonamides, tetracyclins, anti-mycobacterial agents, as well as chloramphenicol, fosfomycin, linezolid, metronidazole, cin, rifamycin, thiamphenicol and tinidazole.
In one embodiment, a nd of the invention is inistered with r therapeutic agent for the treatment and/or prevention of vasculitis, particular agents include but are not limited to steroids (for example prednisone, prednisolone), cyclophosphamide and eventually antibiotics in case of cutaneous infections (for example cephalexin) In one ment, a compound of the invention is co-administered With r therapeutic agent for the treatment and/or tion of IPF, ular agents include but are not limited to pirfenidone and bosentan.
In one embodiment, a compound of the invention is co-administered With another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, particular agents include but are not limited to: betaZ-adrenoceptor agonists (e. g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. opium bromide), glucocorticoids (oral or inhaled) Long-acting BZ-agonists (e.g. salmeterol, formoterol, bambuterol, and ned-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e. g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), tors of mediator release (e.g. lycate and ketotifen), phosphodiesterase-4 inhibitors (e.g. Roflumilast), biological regulators of IgE response (e.g. umab), antihistamines (e.g. zine, cinnarizine, fexofenadine), and vasoconstrictors (e.g. oxymethazoline, thazoline, nafazoline and tramazoline).
Additionally, a compound of the invention may be administered in combination With emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined With an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e. g. hrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), xanthines (theophylline, aminophylline, bamiphylline), tion anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.
] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD); particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, modulatory agents (e.g. rexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and ciclosporin) and biological disease ing, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
By co-administration is included any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime, as will be nt to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation this is not essential. The agents may be administered in different formulations and at different times.
GENERAL SYNTHETIC PROCEDURES General A compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred s conditions (i.e., on temperatures, times, mole ratios of nts, ts, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[00207] Additionally, as will be nt to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and ection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley- Blackwell; 4th Revised edition edition (2006), and references cited therein.
] The following methods are presented with details as to the preparation of representative 6,7- dihydro-pyrimido[6,1-a]isoquinolinone that have been listed hereinabove. A compound of the invention may be prepared from known or commercially ble starting materials and reagents by one skilled in the art of organic synthesis.
[00209] All reagents were of commercial grade and were used as received t r purification, unless otherwise stated. Commercially available anhydrous solvents were used for ons conducted under inert atmosphere. Reagent grade ts were used in all other cases, unless otherwise specified. Column chromatography was performed on silica standard (30-70 um). Thin layer chromatography was carried out using pre-coated silica gel 60 F-254 plates (thickness 0.25 mm). 1H NMR spectra were recorded on a Bruker e 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz).
Chemical shifts (5) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (5 0.00) or the appropriate al solvent peak as internal reference. Multiplicities are given as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), t (q), multiplet (m) and broad (br). Electrospray MS a were obtained either on a Waters platform LC/MS spectrometer or on an Agilent 1100 Series . Analytic LCMS: Columns used, Waters Acquity UPLC BEH C18 1.7um, 2.1mm ID x 50mm L or Waters Acquity UPLC BEH C18 1.7um, 2.1mm ID X 30mm L or Waters XBridge C18 3.5um, 2.1mm ID X 50mm L. All the methods are using MeCN/H20 gradients. MeCN and H20 contain either 0.1% Formic Acid or NH3 (10mM). ative LCMS: Column used, Waters XBridge Prep C18 Sum ODB 30mm ID x 100mm L. All the methods are using either MeOH/HZO or MeCN/H20 gradients. MeOH, MeCN and H20 contain either 0.1% Formic Acid or 0.1 % Diethylamine. Analytic chiral LC: Column used, Chiralpak IA 5 um 250 x 4.6 mm. Microwave heating was med with a Biotage Initiator.
Table I: List of abbreviations used in the mental section: r‘ microliter DMAP 4-Dimethylaminopyridine DME D1methoxyethane Acetic acid DMF N,N-dimethylformamide g5 aqueous DMSO Dimethylsulfoxide ATP ine 5 '-Triphosphate Dulbecco's Phosphate-Buffered 2,2 -b1s(d1phenylphosph1n0)-1 ,1 - DPBS BINAP Saline binaphthyl 1,1’- Boc tert-Butyloxy—carbonyl DPPF phenylphosphino)ferrocene BocZO Di-lerZ-butyl dicarbonate EtOAc Ethyl acetate br s broad singlet EtZO Diethyl ether Calcd calculated equivalent Cat. Catalytic amount gram doublet guanosine 5'—O-[gamma- Doublet of doublet thiO]triphosphate hour DCC N,N’-Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane Heptane DCM Dichloromethane High-performance liquid chromatography DIAD Diisopropyl azodicarboxylate 1sopropanol.
DIPEA N,N—diisopropylethylamine Diisopropyl ether 2012/076275 KHMDS Potassium hexamethyldisilazane obsd observed Liquid Chromatography- Mass Pd(OAc)2 Palladium(H) acetate LCMS Spectrometry Tetrakis(triphenylphosphine)palladi Pd(PPh3)4 Liter um(0) multiplet Pd/C Palladium on Carbon 10% Methanol ppm part-per-million Acetonitrile quadruplet Methyl iodide 76%H8 revolutions per minute Methyl ethyl ketone Room ature (IQ milligram retention time minute 2-Dicyclohexylphosphino-2',6'-di-i- propoxy- 1 ,1 '-biphenyl milliliter millimole mE Starting material mass spectrometry Scintillation proximity assay Z2 Molecular weight Solid phase extraction Molecular weight calculated (calc) sodiumtriacetoxyborohydride MW (obs) Molecular weight observed II triplet Nicotinamide adenine dinucleotide E Tetra-n-butylammonium fluoride NADP ylamine %i Non-Essential Amino Acid Trifluoroacetic acid N—Methyl-Z-pyrrolidone Tetrahydrofuran Nuclear Magnetic Resonnance Thin layer chromatography l Synthetic Method ediates The intermediates to prepare the compounds according to the invention can be produced according to the following schemes.
J::l\/\ 0 \ J::l\/\ JL \0 NH2 0 fl NH2 Intermediate 1 Intermediate 2 CI 1 4L I J::l\/\ 0 O N <— v0 NJLNH v JL / o N NH2 O/\/ 0M0 H Intermediate 5 Intermediate 4 Intermediate 3 O/fi 0/fi 0/fi kfo K/O kgo N / N/ N / a ' I I N oéLN 4kN Qmif OH O "0 compound 118 Intermediate 6 Intermediate 9 0/} 0/} o KIO K10 KIO O O O N / N / N/ | A I I N o N N 0.. k': OH 0' "0 compound 117 Intermediate 7 Intermediate 10 0N 0N ofi Y Y Y o O o N’ N/ N’ I I N o N oél‘N I o, OH 0' - compound 1 ediate 8 Intermediate 11 Intermediate 1: [2-(3-methoxy-phenyl)-ethyl]-urea A solution of 3-methoxyphenethylamine (100 g, 661.3 mmol, 1 eq.), urea (157.3 g, 2619.0 mmol, 4 eq.), AcOH (36 mL) and aq. HCl (12 mL) in H20 (800 mL) was heated under reflux for 5 days. The reaction mixture was cooled to RT, the solid was d off, washed with water and dried to afford intermediate 1. (1H, CDC13) 5 (ppm): 7.24 (1H, t), 6.82-6.77 (3H, m), 5.10 (1H, br s), 4.52 (2H, br), 3.81 (1H, s), 3.42 (2H, br t), 2.80 (2H, t) Intermediate 2: [2-(3-hydr0xy-phenyl)—ethyl]-urea A solution of ediate 1 (72 g, 370.7 mmol) in concentrated HBr (500 mL) was heated under reflux overnight. The reaction mixture was brought to basic pH by addition of NaHC03 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under vacuum to afford ediate 2. (1H, MeOD-d4) 5 (ppm): 7.15 (1H, t), 6.76-6.68 (3H, m), 3.40-3.36 (2H, t), 2.77—2.74 (2H, t) Intermediate 3: [2-(3-allyloxy-phenyl)-ethyl]-urea To a solution of intermediate 2 (45 g, 249.7 mol, 1 eq.) and K2C03 (103.5 g, 749.1 mmol, 3 eq.) in anhydrous DMF (300 mL) under a en atmosphere, was added allylbromide (50.5 mL, 499.4 mol, 2 eq.). The reaction e was stirred for 2.5 days, then DMF was evaporated to dryness. The residue was dissolved in EtOAc, washed with saturated Na2C03, brine, dried over MgSO4 and trated under vacuum to afford intermediate 3. (1H, 4) 6 (ppm): 7.24 (1H, t), 6.87-6.81 (3H, m), 6.16-6.06 (1H, m), 5.45 (1H, dd), 5.29 (1H, dd), 4.59-4.57 (2H, m), 3.38 (2H, t), 2.80 (2H, t) Intermediate 4: 1-[2-(3-allyloxy-phenyl)-ethyl]-pyrimidine-2,4,6-tri0ne Sodium (20.06 g, 872 mmol, 1 eq.) was dissolved in EtOH (1.4 L). Diethyl malonate (132.4 mL, 872 mol, 1 eq.) was added and the reaction e was heated under reflux for 1h. Intermediate 3 (96 g, 436 mmol, 0.5 eq.) in EtOH (300 mL) was added and the reaction mixture was heated under reflux for 12 h.
The reaction was cooled to RT, 1N aq. HCl was added and the precipitate was filtered, washed with water and dried to afford intermediate 4. (1H, CDC13) 8 (ppm): 8.40 (1H, br s), 7.25 (1H, t), 6.88-6.82 (3H, m), 6.14-6.04 (1H, m), 5.45 (1H, dd), 5.32 (1H, dd), 4.58-4.56 (2H, m), 4.13 (2H, t), 3.64 (2H, s), 2.92 (2H, t) MW (calcd): 288.3; MW (obsd): 289.3 (M + 1) Intermediate 5: 9-allyloxychlor0-6,7-dihydr0-pyrimid0[6,1-a]isoquinolin0ne A solution of intermediate 4 (20 g, 69.4 mol, 1 eq.) in POC13 (150 mL) was stirred at 50°C for 3 days. POC13 was evaporated under vacuum and the residue was dissolved in DCM and quenched with saturated NaHCOg. The organic layer was washed with water, dried over MgSO4 and concentrated to afford intermediate 5. (1H, CDC13) 6 (ppm): 7.71 (2H, d), 6.97 (1H, dd), 6.86 (1H, d), 6.71 (1H, s), 6.13-6.04 (1H, m), 5.47 (1H, dd), 5.36 (1H, dd), 4.67-4.65 (2H, m), 4.27 (2H, t), 3.05 (2H, t) MW (calcd): 288.7; MW (obsd): 289.3 (M+1) General methods General method A: /\O / ’ N NaH N A | | O N O N To a solution of NaH (2 eq., 60% in mineral oil) in anhydrous DCM at 0°C, is added 2- hydroxymethyl-[1,4]dioxane (2 eq.) with the appropriate chirality, after 15 min, intermediate 5 (1 eq.) is added at 0°C, and the reaction is stirred at RT until completion. Saturated NH4Cl is added to the reaction mixture, the organic layer is washed with water, dried over MgSO4 and concentrated. The desired product is purified by flash chromatography on silica gel. 2-Hydroxymethyl-[1,4]dioxane, (R) 2-hydroxymethyl-[1,4]dioxane and (S) 2-hydroxymethyl- [1,4]dioxane are commercially ble or can easily be prepared [Young Kim er al ; Bioorganic & Medicinal Chemistry 15 (2007) 2667—2679].
Illustrative sis of general method A: Compound 118: 9-allyloxy((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one A on of (R) 2-hydroxymethyl—[1,4]dioxane (56.6 g, 479 mmol, 2 eq.) and NaH (19.9 g, 479 mol, 2 eq., 60% in mineral oil) in anhydrous DCM (300 mL) was stirred for 30 min at 0°C. Intermediate 5 (69.2 g, 240 mol, 1 eq.) in solution in anhydrous DCM (700 mL) was added at 0°C. The on e was stirred for 2 h. Saturated NH4C1 was added, the organic layer was washed with water, dried over MgSO4 and ated to dryness. The crude product was d by flash chromatography on silica gel (MeOH/DCM) to afford compound 118.
(H, CDC13) 8 (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.32 (1H, s), 6.15-6.03 (1H, m), 5.47 (1H, dd), 5.37 (1H, dd), 4.65-4.63 (2H, m), 4.51-4.39 (2H, m), 4.23 (2H,t), 4.06-3.98 (1H, m), 3.92-3.47 (6H, m), 3.01 (2H, t) Compound 1: 9-allyloxy([1,4]dioxan—2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone Compound 1 was prepared using general method A starting from 2-hydr0xymethyl-[1,4]di0xane. (1H, CDC13) 6 (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.32 (1H, s), 6.11-6.04 (1H, m), 5.47 (1H, dd), 5.35 (1H, dd), 4.65-4.63 (2H, m), 4.491-4.40 (2H, m), 4.22 (2H, t), 4.02-3.99 (1H, m), .46 (6H, m), 3.00 (2H, t) MW (calcd): 370.4; MW (obsd): 371.4 (M+1) Compound 117: loxy((R)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one
[00221] nd 117 was prepared using general method A starting from (S) 2-hydr0xymethyl- [1,4]dioxane. (1H, CDC13) 5 (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.31 (1H, s), 6.12-6.04 (1H, m), 5.49 (1H, dd), 5.36 (1H, dd), 4.65-4.63 (2H, m), 4.50-4.42 (2H, m), 4.23 (2H, t), 4.04-4.00 (1H, m), 3.91-3.50 (6H, m), 3.01 (2H, t) MW (calcd): 370.4; MW (obsd): 371.2 (M+1) General method B: 0 (150fi o/ 0/ j]: I Pd(PPh3)4, K2C03 N/ —> | O N O N To a suspension 0fc0mp0und 1, 117 or 118 (1 eq.) in a mixture of DCM/MeOH (1/1) is added K2CO3 (2 eq.) and Pd(PPh3)4 (0.05 eq.). The reaction e is degassed before stirring at RT. After completion, water is added to the reaction mixture and the s layer is separated. The pH of the aqueous solution is adjusted to pH 1 with 2M aq. HCl. The precipitate is filtered off, washed with water and dried to afford intermediate 6, 7 0r 8.
Illustrative sis of general method B: Intermediate 6: 2-((S)[1,4]dioxanylmethoxy)hydroxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one To a suspension of compound 118 (31.15 g, 84.2 mmol, 1 eq.) in a mixture of OH (1/ 1, 800 mL) was added K2C03 (23.2 g, 138.2 mol, 2 eq.) and Pd(PPh3)4 (4.86 g, 4.21 mmol, 0.05 eq.). The reaction mixture was stirred at RT for 2 h. Water (800 mL) was added, and the aqueous layer was separated.
The pH of the aqueous solution is adjusted to pH 1 with 2 M aq. HCl. The precipitate was filtered off, washed with water and dried to afford intermediate 6. (1H, DMSO-d6) 6 (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45 (1H, s), 4.25-4.23 (2H, m), 3.99 (2H, t), 3.87-3.75 (3H, m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.30 (1H, m), 2.91 (2H, t) MW ): 330.4; MW : 331.3 (M+1) Intermediate 7: 2-((R)[1,4]dioxanylmeth0xy)hydr0xy-6,7-dihydr0-pyrimid0[6,1-a]is0quin01in- 4-0ne Intermediate 7 was prepared using l method B starting from nd 117 . (1H, DMSO-d6) 8 (ppm): 7.83 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.44 (1H, s), 4.27-4.20 (2H, m), 3.98 (2H, t), .74 (3H, m), 3.68-3.57 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t) Intermediate 8: 2-([1,4]dioxanylmeth0xy)hydr0xy-6,7-dihydr0-pyrimid0 [6,1-a]is0quinolin0ne Intermediate 8 was prepared using general method B starting from compound 1. (1H, DMSO-d6) 6 (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45 (1H, s), .20 (2H, m); 3.99 (2H, t), .73 (3H, m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t) MW (calcd): 330.4; MW (obsd): 331.0 (M+1) General method C:
[00226] A solution of intermediate 6, 7 or 8 (1 eq.), N—phenyl-bis(trifluoromethanesulfonimide) (1.2 eq.) and Et3N (1.3 eq.) in DCM under nitrogen is stirred at RT until completion. The reaction e is concentrated and the crude is purified by crystallization from iPrOH to afford intermediate 9, 10 or 11.
Illustrative synthesis of general method C: Intermediate 9: trifluoro-methanesulfonic acid 2-((S)[1,4]dioxanylmeth0xy)0x0-6,7-dihydr0- 4H-pyrimid0 [6,1-a]is0quinolinyl ester A solution of intermediate 6, (24 g, 72.7 mol, 1 eq.), N—phenyl-bis(trifluoromethanesulfonimide) (31.15 g, 87.2 mmol, 1.2 eq.) and Et3N (13.2 mL, 94.4 mmol, 1.3 eq.) in DCM (700 mL) under a nitrogen atmosphere is stirred at RT overnight. The reaction mixture is concentrated. The crude is taken in iPrOH (75 mL) heated under reflux and cool to RT. After two days at RT, the solid is filtered off and dried to afford intermediate 9. (1H, CDC13) 8 (ppm): 7.83 (1H, d), 7.35 (1H, dd), 7.29 (1H, d), 6.41 (1H, s), 4.51-4.42 (2H, m), 4.28 (2H, t), 4.06-4.01 (1H, m), 3.89-3.69 (5H, m), 3.52 (1H, m), 3.11 (2H, t) Intermediate 10: trifluoro-methanesulfonic acid 2-((R)[1,4]dioxanylmethoxy)oxo-6,7-dihydro- 4H-pyrimido [6,1-a]isoquinolinyl ester Intermediate 10 was prepared using general method C starting from intermediate 7.
(H, CDC13) 8 (ppm): 7.83 (1H, d), 7.34 (1H, dd), 7.29 (1H, d), 6.41 (1H, s), 4.51-4.41 (2H, m), 4.28 (2H, t), 4.05-4.00 (1H, m), 3.91-3.66 (5H, m), 3.52 (1H, t), 3.11 (2H, t) Intermediate 11: trifluoro-methanesulfonic acid 2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H- pyrimido [6,1-a]isoquinolinyl ester Intermediate 11 was prepared using l method C starting from intermediate 8. (1H, DMSO-d6) 5 (ppm): 8.21 (1H, d), 7.65 (1H, d), 7.54 (1H, dd), 6.75 (1H, s), 4.28-4.26 (2H, m), 4.04 (2H, t), 3.90-3.84 (1H, m), 3.81-3.75 (2H, m), 3.68-3.58 (2H, m), 3.53-3.47 (1H, m), .36 (1H, m), 3.10 (t, MW (calcd): 462.4; MW (obsd): 463.3 (M+1) 0/0 O/\ o/\ K/O KKO go o’ 0’5 o’ | N / | N / A F | O N Q. kl: Step 1 CAN Step 2 CAN .8" F O _> o N | Intermediate 9 Intermediate 12 Intermediate 13 ediate 13: 9-amino((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one hydrochloride Step I .' 9-(Benzhydrylidene-amin0)((S)-I -[I,4]dioxan-Z-ylmethoxy)-6, 7—dihydr0-pyrimid0[6,1 - ajisoquinolin0ne (Intermediate 12) ] A solution of intermediate 9 (1 g, 2.16 mol, 1 eq.), )2 (24 mg, 0.11 mmol 0.05 eq.), CsZC03 (2.11 g, 6.48 mmol, 3 eq.) BINAP (134 mg, 0.21 mmol, 0.1 eq.) and benzophenonimine (587 mg, 3.24 mmol, 1.5 eq.) in toluene (20 mL) was heated at 150°C in a microwave for 45 min. The solvent was evaporated to dryness and the crude mixture was taken in water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under vacuum. 9-(Benzhydrylidene-amino)((S)[1,4]dioxan ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone intermediate 12 was obtained after purification by flash chromatography on silica gel and ately used in next step.
Step 2: 9-amin0((S)-I -[I,4]di0xanylmeth0xy)-6, 7—dihydr0-pyrimid0[6, I -a]is0quinolin0ne hydrochloride (Intermediate 1 3) ] To a solution of intermediate 12 in a minimum of DCM/ Et20 was added HCl 2N in EtZO (4 mL).
The precipitate was filtered off and dried to afford intermediate 13.
(H, DMSO-d6) 6 (ppm): 7.82 (1H, d), 7.45 (3H, br), 6.68 (1H, d), 6.67 (1H, s), 6.51 (1H, s), 4.32 (2H, d), 3.99 (2H, t), 3.90-3.84 (1H, m), 3.82-3.35 (6H, m), 2.88 (2H, t) MW (calcd): 329.4; MW (obsd): 330.2 (M+1) General method D: / + BrVBF3K _, K K,OVBF3K The corresponding l (2 eq.) is added to a solution of NaH (2 eq., 60% in mineral oil) in THF at 0 °C. The reaction is warmed to RT for 30 min then cooled again at 0 °C. Bromo methyltrifluoroborate (1 eq.) is added to the reaction in one portion and the mixture is stirred at RT from few hours to 3 days (monitoring by R). The reaction is quenched with a solution of KHFZ (1.5 M, 3 eq.) and the mixture is evaporated to dryness. The residue is suspended in acetone, the inorganics are filtered off and the filtrate is evaporated to dryness. The residue is suspended in a minimum amount of acetone, EtzO is added and the product is obtained by filtration. rative s nthesis 0f eneral method D: Intermediate 14: tetrahydro-2H-pyran01-methyl trifluoroborate (5 KBF O BrVBFsK 3V Intermediate 14
[00234] Tetrahydro-pyranol (152 mg, 1.49 mmol, 2 eq.) was added to a solution ofNaH (60 mg, 1.49 mol, 2 eq., 60% in mineral oil) in THF (4 mL) at 0 °C. The reaction was warmed to RT for 30 min then cooled again at 0 °C. Bromo methyltrifluoroborate (150 mg, 0.75 mol, 1 eq.) was added to the reaction in one portion and the mixture was stirred at RT for 1 day (monitoring by 19F-NMR). The on was ed with a solution of KHFZ (1.5 mL, 1.5 M, 3 eq.) and the mixture was evaporated to dryness. The residue was suspended in acetone, the nics were filtered off and the filtrate was evaporated to dryness.
The residue was ded in a minimum amount of acetone (1.5 mL), and EtZO (6 mL) was added.
Intermediate 14 was obtained by filtration. (1H, DMSO-d6) 5ppm 3.78 (2 H, d), 3.31 - 3.21 (2 H, m), 3.18 - 3.08 (1 H, m), 2.50 - 2.45 (2 H, m), 1.86 - 1.74 (2 H, m), 1.34 - 1.19 (2 H, m) Intermediate 15: potassium oxetanemethyltrifluoroborate b KBF O BF3KVBr 3V v Intermediate 15 Intermediate 15 was prepared Via general method D with oxetanol (the trifluoroborate reagent was recovered with the inorganics rather than the e). (1H, DMSO-d6) 5 ppm 4.56 (2 H, s), 4.32 (3 H, d), 2.40 (2 H, (1) Intermediate 16: potassium (3-methylmethyloxy-oxetane-methyltrifluoroborate + HO\/€/o r _ \/€/o Intermediate 16 Intermediate 16 was prepared Via general method D with (3-methyloxetanyl) methanol (the trifluoroborate reagent was recovered with the nics rather than the filtrate). (1H, 6) 5 ppm 4.34 (2 H, d), 4.14 (2 H, d), 3.26 (2 H, s), 2.59 _ 2.52 (2 H, m), 1.19 (3 H, 5) Intermediate 17: potassium 2,2-dimethyl-propyloxy-methyltrifluoroborate BF3KVBr + [40% I KBF3\/O\/¥ Intermediate 17
[00237] Intermediate 17 was prepared Via general method D with 2,2-dimethyl—pr0panol. (1H, DMSO-d6) 5 ppm 2.88 (2 H, s), 2.51 - 2.45 (2 H, m), 0.83 (9 H, 5) Intermediate 18: potassium cyclopropylmethoxy-methyltrifluoroborate BF3KVBF + HO\/A KBF3VO\/A Intermediate 18
[00238] Intermediate 18 was prepared Via general method D wOith cyclopropyl-methanol. (1H, DMSO-d6) 5 ppm 3.00 (2 H, d), 2.46 (2 H, d), 1.00 - 0.82 (1 H, m), 0.46 - 0.31 (2 H, m), 0.13 - 0.00 (2 H, m) Intermediate 19: cyclopentylmethoxy-methyltrifluor0b0rate BFsKVBr + HO\/O , KBF3VO\/O Intermediate 19 ] Intermediate 19 was prepared Via general method D with cyclopentyl-methanol. (1H, 6) 5 ppm 3.04 (2 H, d), 2.46 (2 H, d), 2.08 — 1.94 (1 H, m), 1.47 (6 H, br. s.), 1.07 - 1.22 (2 H, Intermediate 20: potassium 2-cyclopropyl—ethyl—trifluor0b0rate V/\/Br V/\/BF3K Intermediate 20 A 2-neck round bottom flask equipped with a reflux condenser and an addition funnel was charged with Mg (193 mg, 8.05 mol, 3 eq.) and EtZO (1 mL) under N2. One drop of neat (2-bromo-ethyl)- cyclopropane was added followed by two drops of dibromoethane. Once the 1St s appeared, (2-bromoethyl )-cyclopropane (400 mg, 2.68 mmol, 1 eq.) in EtZO (5 mL) was added dropwise. Upon completion of the addition, the resulting suspension was stirred at RT for 1 h. In a separate flask, purged with N2, a solution made of 3 (0.45 mL, 4.02 mmol, 1.5 eq.) in THF (6 mL) was cooled to -78 °C. To this solution, the 2- cyclopropyl—ethyl magnesium e suspension was added dropwise Via a double ended needle. The e was allowed to stir for 1 h at -78 °C and then was warmed to RT for 1 h. After cooling the mixture to 0 °C, a saturated aqueous on of KHF2 (2.5 mL, 4.5 M, 4.1 eq.) was added dropwise and the reaction mixture was allowed to warm to RT. After 30 min, the solution was concentrated in-vacuo. The dried solids were triturated with hot acetone and filtered to remove inorganic salts. The resulting filtrate was concentrated and the solid residue was triturated with EtZO. Potassium 2-cyclopropyl-ethyl-trifluoroborate was filtered and dried in-vacuo. (1H, DMSO-d6) 5 ppm 1.07 — 0.92 (2 H, m), 0.66 - 0.53 (1 H, m), 0.27 - 0.21 (2 H, m), 0.067 - -0.07 (2 H, m), -0.117 - -0.17 (2 H, m) General method E: o/fi o/fi 3° 3° 0 O N/l —’ N/l O N O N OTf Z Intermediate 9, 10, 11 A vial is charged with intermediate 9, 10 or 11 (1 eq.), the appropriate boronic acid, boronic ester or potassium trifluoroborate (4.4 eq.), Cs2C03 (2.6 eq.), (DPPF)PdC12.DCM (0.05 eq.), in oxane/H20 (10/1 , v/v), and the mixture is degassed with N2. The vial is sealed and heated at 80 °C. When the reaction is complete, the vial is cooled to RT and the reaction is either worked up or volatiles are evaporated under . The product is then obtained after purification by either flash tography on silica gel, preparative TLC or preparative HPLC-MS.
Illustrative s nthesis of eneral method E: Compound 2: 2-([1,4]dioxanylmethoxy)pyridinyl-6,7-dihydro-pyrimido [6,1-a]isoquinolinone oN oN ° 5° 0 O O N O N OTf \ Intermediate 11 Compound 2 A vial was charged with intermediate 11 (84 mg, 0.074 mol, 1 eq.), pyridine-3 -boronic acid (40 mg, 0.327 mmol, 4.4 eq.), Cs2C03 (62 mg, 0.190 mmol, 2.6 eq.), PdC12.DCM (3.3 mg, 0.004 mmol, 0.05 eq.), in 1,4-dioxane (1 mL) and H20 (0.1 mL), and the mixture was degassed with N2. The vial was sealed and heated at 80 °C. After 1h, the vial was cooled to RT and volatiles were evaporated under vacuum.
The residue was then purified by flash tography on silica gel, eluting with 7.5% MeOH/DCM to afford compound 2. (1H, CDC13) 5 ppm 8.89 (1 H, s), 8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1 H, d), 7.61 (1 H, d), 7.53 (1 H, s), 7.43 (1 H, dd), 6.43 (1 H, s), 4.51 - 4.37 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, m), 3.92 - 3.60 (5 H, m), 3.49 (1 H, m), 3.10 (2 H, t) General method F: o/fi o/fi 3° 3° 0 O N / —> N / I I O N O N OH O’Y ediate 6, 7, 8 A solution of intermediate 6, 7, 0r 8 (1 eq.), the appropriate alkylating agent (1.5 eq.), K2C03 (2 eq.), KI (1 eq.) in MEK is heated at 80 °C. When the reaction is complete, the volatiles are evaporated to dryness and the residue is purified by flash chromatography on silica gel to give the desired product.
Illustrative s nthesis of eneral method F: Compound 8: 2-([1,4] dioxanylmethoxy)(oxazolylmethoxy)-6,7-dihydro-pyrimido [6,1- uinolinone ON ON T 5° 0 O A A O N O N OH O Intermediate 8 Compound 8 A solution of intermediate 8 (40 mg, 0.12 mol, 1 eq.), 2-ch10r0methy10xazole (21 mg, 0.18 mmol, 1.5 eq.), K2CO3 (33 mg, 0.24 mmol, 2 eq.), KI (20 mg, 0.12 mmol, 1 eq.) in MEK (2 mL) was heated at 80 °C for 16 h. The reaction was evaporated to dryness and the residue was d by flash chromatography on silica gel, eluting with 4% CM to give compound 8. (1H, CDC13) 6 ppm 7.72 (1 H, d), 7.68 - 7.60 (1 H, m), 7.18 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.23 (2 H, s), 4.49 — 3.94 (1 H, m), 3.89 - 4.33 (2 H, m), 4.19 (2 H, t), 4.02 - 3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t) MW (calcd): 411.4; MW (obsd): 412.4 (M+1) General method G: 3° 3° 0 O O N OAN OTf § Intermediate 9, 10, 11 Intermediate 9, 10, 11 (1 eq.) is dissolved in DMF, the appropriate alkyne (3 eq.) is added followed by TEA (3.5 eq.), and the e is ed. Pd(PPh3)3C12 (0.05 eq.) is added with CuI (0.2 eq.) and the reaction mixture is heated at 80 °C. When the reaction is gone to completion, it is cooled to RT and either worked up or volatiles are evaporated to dryness. The product is then obtained after purification by either flash chromatography on silica gel, preparative TLC or ative HPLC-MS.
Illustrative s nthesis of eneral method G: Compound 16: 2-([1,4] dioxan—2-ylmeth0xy)—9-(1-methyl-1H-imidazol—2-ylethynyl)-6,7-dihydr0- pyrimido [6,1-a]isoquinolin0ne ON ON O 0 j: —’ | j: | O N O N OTf % N Intermediate 11 Compound 16 Intermediate 11 (1.4 g, 3.03 mol, 1 eq.) was ved in DMF (20 mL), 5-ethynylmethyl-1H- imidazole (0.92 mL, 9.09 mmol, 3 eq.) was added ed by TEA (1.48 mL, 10.61 mmol, 3.5 eq.). The mixture was degassed and 3)3C12 (106 mg, 0.15 mmol, 0.05 eq.) was added with CuI (115 mg, 0.61 mmol, 0.2 eq.). The reaction mixture was heated at 80 °C for 16 h. The reaction was cooled to RT and quenched with brine, the mixture was then extracted with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated under vacuum. The crude product was then purified by flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM to give compound 16.
WO 92791 (1H, CDC13) 5 ppm 7.73 (1 H, d), 7.57 - 7.50 (2 H, m), 7.48 - 7.45 (1 H, m), 7.42 (1 H, d), 6.42 (1 H, s), 4.53 - 4.39 (2 H, m), 4.28 - 4.23 (2 H, m), 4.07 - 3.97 (1 H, m), 3.94 - 3.64 (8 H, m), 3.52 (1 H, dd), 3.06 (2 H, t) MW (calcd): 418.4; MW (obsd): 419.4 (M+1) General method H: o/fi o/fi :0 30 O 0 oil | —’ o”; I % v % v OH 0\ tBuOK (3 eq.) is added to a solution of the corresponding acetylenic alcohol (1 eq.) in THF, Mel (10 eq.) is then added and the reaction is d at RT. When the reaction has gone to completion, the reaction mixture is filtered and the filtrate is evaporated to dryness. Product is obtained after ation by preparative TLC.
Illustrative s nthesis 0f eneral method H: nd 110: 2-([1,4]dioxan-Z-ylmeth0xy)(3-meth0xymethyl-pentynyl)-6,7-dihydr0- pyrimido [6,1-a]isoquinolin0ne o/\ o/\ 80 50 O O N / N / DAN | —> CAN | % % OH 0\ Compound 91 Compound 110 tBuOK (5.19 mg, 0.046 mmol, 0.95 eq.) was added to a solution of compound 90 (20 mg, 0.049 mmol, 1 eq.) in THF (2 mL), Mel (0.030 mL, 0.487 mmol, 10 eq.) was then added and the reaction was d at RT for 16 h. Some more tBuOK (11 mg, 0.097 mmol, 2 eq.) was added and the reaction was stirred for an extra day. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by preparative TLC eluting with 2% MeOH/DCM to yield compound 110. (1H, CDC13) 6 ppm 7.70 - 7.60 (1 H, d), 7.50 - 7.42 (1 H, d), 7.39 (1 H, s), 6.37 (1 H, s), 4.50 - 4.35 (2 H, m), 4.25 - 4.15 (2 H, m), 4.05 - 3.95 (2 H, m), 3.92 - 3.60 (5 H, m), 3.56 - 3.45 (4 H, m), 3.05 - 3.95 (2 H, m), 2.15 - 1.95 (1 H, m), 1.15 - 1 (6 H, t) MW (calcd): 424.5; MW (obsd): 425.2 (M+1) General method I: :0 o 0 Q Axl _. N’| O N O N %U U A vial is charged with Pd/C (10% w/w) and a solution of the appropriate alkyne (1 eq.) in MeOH is added. The system is purged with N2 before being filled with H2 then the reaction is stirred at RT until completion. The reaction is filtered through Celite and the filtrate is evaporated to dryness. Clean product is obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative HPLC-MS. rative s s of eneral method I: Compound 116: 2-([1,4]di0xanylmeth0xy)(3-hydr0xypyridin—3-yl-pr0pyl)-6,7-dihydr0- do [6,1-a]isoquinolin0ne o90 oél‘N I N/ —> A I O N / % | \ IN Compound 108 Compound 116 A vial was charged with Pd/C (9 mg, 10% w/w) and a solution of compound 108 (87 mg 0.20 mol, 1 eq.) in MeOH (10 mL) was added. The system was purged with N2 before being filled with H2 then the reaction was d for 16 h at RT. The reaction was filtered through Celite and the filtrate was evaporated to s. The crude product was purified by preparative HPLC-MS to give compound 116.
WO 92791 (1H, CDC13) 6 ppm 8.60 - 8.48 (2 H, m), 7.73 (1 H, d), 7.61 (1 H, d), 7.30 (1 H, dd), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.77 (1 H, dd), 4.47 - 4.33 (2 H, m), 4.18 (2 H, t), 3.97 (1 H, m), 3.90 - 3.60 (5 H, m), 3.48 (1 H, t), 2.96 (2 H, t), 2.90 — 1.98 (1 H, m), 1.38 (1 H, t) - 2.70 (2 H, m), 2.15 (1 H, m), 2.10 MW (calcd): 449.5; MW (obsd): 450.1 (M+1) General method J: O; 0; j: | —> I| o N o N NH2.HC| H’T ediate 13 Intermediate 13 (1 eq.) is dissolved in DMF, the appropriate aldehyde (4 eq.) is added followed by KOH (1 eq.). The reaction is stirred for 15 min at RT before STAB (10 eq.) is added, the mixture is then stirred at RT until completion of the reaction. The mixture is then quenched with brine, extracted with EtOAc, the organic layer is dried over MgSO4 and evaporated to s. cation by preparative HPLC- MS affords the corresponding product.
Illustrative synthesis of general method J: Compound 126: 9-(2,2-dimethyl-butylamino)—2-((S)[1,4]dioxanylmethoxy)-6,7-dihydropyrimido [6,1-a]isoquinolinone Co 0” \... \.
O O N / / O N O N NH .HCI 2 H/><\N Intermediate 13 Compound 126 Intermediate 13 (50 mg, 0.14 mol, 1 eq.) was dissolved in DMF (2 mL), 2,2-dimethylbutanal (56 mg, 0.56 mmol, 4 eq.) was added followed by KOH (8 mg, 0.14 mol, 1 eq.). The reaction was stirred for 15 min at RT before STAB (297 mg, 1.40 mmol, 10 eq.) was added, the mixture was then stirred for 2 days at RT. The on was quenched with brine and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and evaporated to dryness. The crude product was purified by preparative HPLC-MS to give compound 126.
(H, CDC13) 6 ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48 (1 H, s), 6.21 (1 H, s), 4.47 - 4.34 (2 H, m), 4.21 - 4.14 (2 H, m), 4.01 — 3.91 (1 H, m), 3.89 - 3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, s), 2.90 (2 H, t), 1.36 (2 H, dd), 0.96 (6 H, s), 0.87 (3 H, t) MW (calcd): 413.5; MW (obsd): 414.4 (M+1) General method K: 05 ° 05 b0 0 o? o/E O; I N / 1 W 1 —> / O It / F —’ ¢ o N N ofs/kFF o N O \\O \\ OH \\ O\ Intermediate 9 Intermediate 15 Step I : 2-((S)-I-[I,4]di0xanylmeth0xy)(3-hydr0xy-pr0p-I-ynyl)-6, 7-dihydr0-pyrimid0[6,1- uinolin0ne (Intermediate 15) Intermediate 15 2-((S)[1,4]dioxanylmethoxy)(3-hydroxy-propynyl)-6,7-dihydro- pyrimido[6,1-a]isoquinolinone was synthesised via general method E with intermediate 9 and propyn- 1-ol.
Step 2: ] Intermediate 15 (1 eq.) is dissolved in a e of THF/DMF (1/ 1), NaH (1.1 eq., 60% in mineral oil) is added followed by the appropriate alkylating agent (1 eq.) and the reaction is stirred at 70 °C. When the reaction has gone to completion, the mixture is worked up with brine and EtOAc, the c layer is dried over MgSO4 and evaporated to dryness. Purification by preparative HPLC-MS es the corresponding product.
Illustrative synthesis of l method K: Compound 133: [1,4]dioxanylmethoxy)[3-(2-methoxy-ethoxy)-propynyl]-6,7-dihydropyrimido [6,1-a]isoquinolinone go O.
O/: o/ ‘ N / 0%N CAN ‘ \ OH \\ O\/\O/ Intermediate 15 Compound 133
[00255] Intermediate 15 (92 mg, 0.25 mol, 1 eq.) was dissolved in a mixture of THF/DMF (6 mL, 1/ 1), NaH (11 mg, 0.275 mmol, 1.1 eq., 60% in mineral oil) was added followed by 1-bromomethoxy—ethane (35 mg, 0.25 mol, 1 eq.) and the reaction was stirred at RT for 16 h, then at 70 °C for 1 day. The mixture was worked up with brine and EtOAc, the organic layer was dried over MgSO4 and ated to dryness.
The crude product was purified by preparative HPLC-MS to provide compound 133. (1H, CDCl3) 5 ppm 7.64 (1 H, s), 7.48 - 7.40 (1 H, m), 7.40 - 7.35 (1 H, m), 6.40 - 6.34 (1 H, m), 4.47 (4 H, s), 4.28 — 2.95 (2 H, m) - 4.15 (1 H, m), 3.93 - 3.56 (10 H, m), 3.43 (5 H, s), 3.06 MW (calcd): 426.5; MW (obsd): 427.4 (M+1) General method L: o/\ o/\ K/O K/O O; O/é CAN —’ CAN OH OJVI ediate 6 To a solution of tBuOK (2.2 eq.) in DMF is added dropwise a solution of intermediate 6 (1 eq.) in DMF at 0 °C and the mixture is stirred for 1 h. A solution of the appropriate ting agent (10 eq.) in DMF is added dropwise to the previous solution at 0 °C, then the reaction is d at 80 °C. When the reaction has gone to completion, the mixture is cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers are dried over NaZSO4 and evaporated to dryness. The product is isolated by purification by preparative TLC.
Illustrative synthesis of general method L: Compound 158: 9-(2,2-dimethyl-propoxy)((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone o O II I' o N —’ O N OH 0% Intermediate 6 Compound 158
[00257] To a solution oftBuOK (19 mg, 0.166 mmol, 1.1 eq.) in DMF (2 mL) was added dropwise a solution of intermediate 6 (50 mg, 0.151 mol, 1 eq.) in DMF (2 mL) at 0 °C and the mixture was stirred for 1 h. A solution of 1-iodo-2,2-dimethyl—propane (0.021 mL, 0.159 mmol, 1.05 eq.) in DMF (2 mL) was added se to the previous solution at 0 °C, then the reaction was stirred at 80 °C for 1 day. Extra reagents were added, 1-iodo-2,2-dimethyl-propane (0.4 mL, 10 eq.) and tBuOK (19 mg, 0.166 mmol, 1.1 eq.) and the reaction was stirred at 80 °C for one more day. The mixture was cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaZSO4 and ated to dryness. Compound 158 was obtained by purification by preparative TLC [DCM/MeOH, 98/2]. (1H, CDC13)6 ppm 7.70 - 7.56 (1 H, d), 6.95 - 6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1 H, s), 4.50 - 4.35 (2 H, m), 4.25 - 4.10 (2 H, m), 4.05 - 3.92 (1 H, m), 3.10 - 3.57 (8 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H, m), 1.05 (9H, 5).
MW (calcd): 400.5; MW (obsd): 401.2 (M+1) Compounds of the invention The nds according to the ion can be produced as described below.
Compound 1: 9-Allyloxy—2-([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
] Synthesis fiJlly described above.
Compound 2: 2-([1,4]dioxanylmethoxy)-9 -pyridin-3 -yl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
Synthesis fiJlly described above.
Compound 3: 2-([1,4]dioxanylmethoxy)-9 -pyridinyl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
This compound is ed via general method E using intermediate 11 and pyridineboronic acid.
Compound 4: 2-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl] - benzonitrile.
This compound is prepared Via general method E using intermediate 11 and 2- cyanophenylboronic acid.
Compound 5: 3 -[2-([1,4]dioxan-Z-ylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl] - benzonitrile.
This compound is prepared Via general method E using intermediate 11 and 3- cyanophenylboronic acid.
Compound 6: 4-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl] - benzonitrile.
This compound is prepared Via general method E using intermediate 11 and 4- cyanophenylboronic acid.
Compound 7: ,4]dioxan-Z-ylmethoxy)—4-0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyloxy]- acetonitrile.
This compound is prepared Via general method F using intermediate 8 and bromo-acetonitrile, K1 was not used in the ment. nd 8: 2-([1,4]di0xanylmeth0xy)(0xazolylmeth0xy)-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne.
] Synthesis fiJlly described above.
Compound 9: 2-([1 ,4]di0xanylmeth0xy)—9-(pyridinylmeth0xy)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quinolin0ne.
] This compound is ed Via general method F using intermediate 8 and pyridin-Z-yl-methanol hydrochloride.
Compound 10: 9-(3 ,5 -dichlor0-phenyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimid0 [6,1 - a]is0quinolin0ne.
This compound is prepared Via general method E using intermediate 11 and 3,5- dichlorophenylboronic acid.
Compound 11: 9-benzofuranyl([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
] This compound is prepared via general method E using ediate 11 and 1-benzofuran ylboronic acid.
Compound 12: 2-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]- indole-l-carboxylic acid tert-butyl ester.
This nd is prepared via general method E using intermediate 11 and t- butoxycarbonyl)- 1 H-indolylboronic acid.
Compound 13: 2-([1,4]dioxanylmethoxy)(1H-indol—2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
Compound 12 Compound 13 Compound 12 (57 mg, 0.11 mmol) was dissolved in a mixture of DCM/TFA (1/ 1, 2 mL) and the reaction was stirred at RT for 6h. The e was evaporated to dryness to recover compound 13 as a TFA salt. (1H DMSO-da) 8 ppm 8.11 (1 H, d), 7.95 - 7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H, d), 7.15 (1 H, t), 7.10 (1 H, d), 6.71 (1 H, s), 4.31 - 4.25 (2 H, m), 4.09 (2 H, t), 3.92 - 3.84 (1 H, m), 3.79 (2 H, td), 3.71 - 3.57 (2 H, m), 3.55 - 3.46 (1 H, m), 3.40 (1 H, dd), 3.08 (2 H, t) MW (calcd): 429.5 MW (obsd): 430.5 (M+1) Compound 14: 2-([1,4]dioxanylmethoxy)-9 -(6-methoxy—pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This compound is prepared via general method E using intermediate 11 and 2-methoxy pyridineboronic acid.
Compound 15: 2-([1,4]di0xanylmeth0xy)(6-triflu0r0methyl—pyridinyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne.
This compound is prepared Via general method E using ediate 11 and 2-(triflu0r0methyl) pyridine-S-boronic acid.
Compound 16: 2 -( [1 ,4] dioxan-Z-ylmeth0xy)-9 -(3 -methyl-3H-imidazol—4-ylethynyl)-6,7-dihydr0 - pyrimido [6,1 -a]is0quinolin0ne.
Synthesis fiJlly described above.
Compound 17: 9-(5-tert-butyl-[1,2,4]0xadiazolylmeth0xy)—2-([1,4]di0xanylmeth0xy)-6,7-dihydr0- do [6,1 -a]is0quinolin0ne.
] This compound is ed Via general method F using ediate 8 and 5-(tert-butyl) (chloromethyl)-1 ,2,4-0xadiazole.
Compound 18: 5-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]- pyridine-Z-carboxylic acid methylamide.
This compound is prepared Via general method E using intermediate 11 and 2-(N— methylaminocarbonyl) pyridine-S-boronic acid pinacol ester.
Compound 19: 2-([1 ,4]di0xanylmeth0xy)pentynyl-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
This compound is prepared Via general method G using intermediate 11 and pent-l-yne.
Compound 20: 2-([1,4]di0xanylmeth0xy)(2-pyridinyl-ethyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne. o/fi o/fi o/fi 3° 3° 3° 0 o o N / N oél‘N | 02‘ Intermediate 11 2 5 Intermediate 22 Compound 20 Step I: 2-([I,4]dt0xanylmeth0xy)((E)pyridtnyl—vinyl)-6,7-dihydr0-pyrtmtd0[6,I-ajisoqutnolt'n one (intermediate 22).
A round bottom flask was charged with ediate 11 (50 mg, 0.11 mol, 1 eq.), 2-Vinylpyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdC12.DCM (4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03 mL, 0.22 mmol, 2 eq.) under N2 then the flask was degassed. DMF (2 mL) was then added and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness, the e was then d by flash chromatography on silica gel, eluting from 0 to 3% MeOH/DCM affording intermediate 22 2-([1 ,4]dioxanylmethoxy)((E)pyridinyl-vinyl)-6,7-dihydro-pyrimido[6, 1 quinolinone. (1H, CDC13) 8 ppm 8.66 - 8.59 (1 H, m), 7.74 - 7.53 (4 H, m), 7.46 (1 H, s), 7.39 (1 H, d), 7.30 - 7.15 (2 H, m), 6.37 (1 H, s), 4.48 — 3.93 (1 H, m), 3.89 - 4.34 (2 H, m), 4.21 (2 H, t), 4.02 - 3.59 (5 H, m), 3.53 - 3.42 (1 H, m), 3.03 (2 H, m) MW (calcd): 417.5; MW (obsd): 418.4 (M+1) Step 2: 2-([I,4]dioxanylmethoxy)-9—(2-pyrtdinyZ-ethyD-6,7—dthydro-pyrtmido[6,I-ajt'soqut'noltn-4—one und 20).
A round bottom flask was charged with intermediate 22 (45 mg, 0.11 mol, 1 eq.), PtOZ (6 mg, 0.025 mmol, 0.23 eq.) and THF (2 mL) was added. The system was purged with N2 before being filled with H2 then the reaction was stirred for 16 h at RT. The reaction mixture was filtered through a SPE guanidine cartridge and the solvent was evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 1 to 10% CM to give compound 20.
(H, CDC13) 5 ppm 8.58 (1 H, dd), 7.66 - 7.56 (2 H, m), 7.22 (1 H, dd), 7.19 - 7.09 (3 H, m), 6.36 (1 H, s), 4.50 — 3.95 (1 H, m), 3.91 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4 H, s), 2.98 (2 H, t) MW (calcd): 419.5; MW : 420.5 (M+1) Compound 21: 2-([1,4]dioxanylmethoxy)(2-pyrazinyl-ethyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
O O 50 50 O O N ’ N ’ 0%N I 0%N I | j/ Intermediate 11 Intermediate 23 Compound 21 Step I .' 2-([I,4]dioxanylmetnoxy)((E)pyraztnyl—vinyl)-6, 7—dihydro-pyrtmtdo[6,1-a]tsoquinoltn one (intermediate 23).
A round bottom flask was charged with intermediate 11 (50 mg, 0.11 mol, 1 eq.), 2-vinyl- pyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdClz.DCM (4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03 mL, 0.22 mol, 2 eq.) under N2 then the flask was degassed. DMF (2 mL) was then added and the reaction 2012/076275 was stirred at 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness, the residue was then purified by flash chromatography on silica gel, eluting from 0 to 4% MeOH/DCM affording intermediate 23 2 -( [1 ,4 ]dioxanylmethoxy)-9 -((E)pyrazinyl-vinyl)-6 ,7-dihydro-pyrimido [6 ,1 -a]isoquinolinone. (1H, CDC13) 8 ppm 8.69 (1 H, m), 8.63 - 8.58 (1 H, m), 8.49 (1 H, m), 7.84 - 7.71 (2 H, m), 7.63 (1 H, d), 7.53 (1 H, s), 7.31 (1 H, s), 6.42 (1 H, s), 4.52 - 4.39 (2 H, m), 4.30 - 4.22 (2 H, m), 4.02 (1 H, dd), 3.93 - 3.63 (5 H, m), 3.52 (1 H, dd), 3.08 (2 H, m) MW (calcd): 418.5; MW (obsd): 419.4 (M+1) Step 2: 2-([I,4]di0xanylmelh0xy)-9—(2-pyrazinyZ-elhyD-6,7—dihydr0-pyrimid0[6,I-ajisoquinoll'n0ne (Compound 21).
] A round bottom flask was charged with intermediate 23 (38 mg, 0.09 mol, 1 eq.), PtOZ (5 mg, 0.021 mmol, 0.23 eq.) and THF (2 mL) was added. The system was purged with N2 before being filled with H2 then the reaction was stirred for 16 h at RT. The reaction mixture was filtered through a SPE guanidine cartridge and the solvent was evaporated to dryness. The crude product was purified by flash chromatography on silica gel, g from 1 to 10% MeOH/DCM to give nd 21.
(H, CDC13) 8 ppm 8.55 (1 H, dd), 8.44 (2 H, dd), 7.63 (1 H, d), 7.22 (1 H, dd), 7.15 (1 H, s), 6.36 (1 H, s), 4.36 - 4.53 (2 H, m), 4.17 - 4.26 (2 H, m), 3.95 - 4.07 (1 H, m), 3.61 - 3.93 (5 H, m), 3.51 (1 H, dd), 3.17 (4 H, s), 2.99 (2 H, t) MW (calcd): 420.5; MW (obsd): 421.5 (M+1) Compound 22: 4]dioxanylmethoxy)(1H-indolyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
This compound is prepared via general method E intermediate 11 and using 5-indolylboronic acid.
Compound 23: 2-([1,4]dioxanylmethoxy)(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one.
This compound is prepared via general method E using intermediate 11 and 2- yphenylboronic acid.
Compound 24: 2-([1,4]dioxanylmethoxy)-9 -(5 -methoxy-pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This nd is prepared via general method E using intermediate 11 and 3-methoxy pyridineboronic acid pinacol ester.
Compound 25: 2-([1,4]di0xanylmeth0xy)(1H-indazol—S-yl)-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin one.
This compound is prepared Via general method E using intermediate 11 and 1H-indazole boronic acid.
Compound 26: 2-([1 ,4]di0xanylmeth0xy)-9 -(4-meth0xy-phenyl)-6,7 -dihydr0-pyrimid0 [6,1 -a]is0quinolin- 4-one.
This compound is prepared Via general method E using intermediate 11 and 4- methoxyphenylboronic acid.
Compound 27: [1,4]dioxanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]- benzamide.
This compound is prepared Via l method E using intermediate 11 and 3- arbonyphenylboronic acid.
Compound 28: 5-[2-([1,4]di0xanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl] fluoro-benzamide.
This compound is ed Via general method E using intermediate 11 and 3-(amin0carb0nyl) fluorobenzeneboronic acid.
Compound 29: N— {3-[2-([1,4]dioxanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl]- phenyl} -acetamide.
This compound is prepared Via general method E intermediate 11 and using 3- acetamidophenylboronic acid.
Compound 30: 9-cyclopr0pylethynyl([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -a]isoquinolin- 4-one.
] This compound is ed Via general method G intermediate 11 and using ethynyl- cyclopropane.
Compound 3 1: 2-( [1 ,4 ]di0xanylmeth0xy)-9 -(1-hydr0xy—cyclopentylethynyl)-6 ,7 -dihydr0-pyrimid0 [6 ,1 - a]is0quinolin0ne.
This compound is ed Via general method G intermediate 11 and using 1-ethynyl- cyclopentanol.
Compound 32: 2-([1,4]dioxanylmethoxy)pyrimidinyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
This compound is prepared Via general method E ediate 11 and using 5-pyrimidinylboronic acid.
Compound 33: 9-cyclohexenyl([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
This compound is prepared Via general method E using intermediate 11 and cyclohexene-l- boronic acid pinacol ester.
Compound 34: 4]dioxanylmethoxy)-9 -(1-methyl-1H-indol-5 -yl)-6,7 -dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared Via general method E using intermediate 11 and 1-methylindole boronic acid pinacol ester.
Compound 35: 2-([1,4]dioxanylmethoxy)-9 -(6-methyl-pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This nd is prepared Via general method E using intermediate 11 and 6-methylpyridin ylboronic acid.
Compound 36: 2-([1,4]dioxanylmethoxy)pyridinylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one.
] This compound is prepared Via general method G using intermediate 11 and 2-ethynyl-pyridine.
Compound 37: 2-([1,4]dioxanylmethoxy)(3 -methoxy-prop -1 -ynyl)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone.
This compound is prepared Via general method G using intermediate 11 and 3-methoxy-propyne. nd 38: 5-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]- pentynenitrile.
This compound is prepared Via general method G using intermediate 11 and -ynenitrile.
Compound 39: 2-([1,4]dioxanylmethoxy)(3 -hydroxy—prop-1 -ynyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
] This compound is prepared Via general method G using intermediate 11 and propynol.
Compound 40: 2-([1,4]dioxanylmethoxy)(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared Via general method G using intermediate 11 and 1-ethynyl methoxy-benzene.
Compound 41: 2-([1,4]dioxanylmethoxy)pyridinylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one.
This compound is prepared Via general method G using intermediate 11 and 3-ethynyl-pyridine Compound 42: 4-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-N— methyl-benzamide.
This compound is prepared Via general method E using intermediate 11 and 4-(N— methylaminocarbonyl)phenylbor0nic acid. nd 43: 2-([1,4]dioxanylmethoxy)(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin- 4-one.
This compound is prepared Via general method E using intermediate 11 and 3- methoxyphenylboronic acid.
Compound 44: hloro-phenyl)([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
This compound is prepared Via general method E using intermediate 11 and 2- chlorophenylboronic acid.
Compound 45: 2-([1,4]dioxanylmethoxy)-9 -(4-hydroxy-but-1 -ynyl)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone.
This compound is prepared Via general method G using ediate 11 and butynol.
Compound 46: 9-(1,5-dimethyl-1H-pyrazolylmethoxy)—2-([1,4]dioxanylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
This compound is ed Via general method F using intermediate 8 and romethyl-1,5- dimethyl- 1 H-pyrazole.
C0mpound 47: 2 -( [1 ,4] dioxanylmethoxy)-9 -(1 -methyl-1H-pyrazol-3 -ylmethoxy)-6,7-dihydro - pyrimido [6,1 -a]isoquinolinone.
This compound is prepared via general method F using intermediate 8 and 3-chloromethyl methyl-1 H-pyrazole.
Compound 48: 2-([1,4]dioxanylmethoxy)(3-methyl-[1,2,4]oxadiazol-S-ylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
This compound is prepared via l method F using intermediate 8 and 5-chloromethyl methyl-[1,2,4]oxadiazole.
Compound 49: 2-([1,4]dioxanylmethoxy)—9-(4-morpholinyl-phenyl)-6,7 ro-pyrimido [6,1 - uinolinone.
This compound is prepared via general method E using intermediate 11 and 4- morpholinophenylboronic acid, with CsF as base and DMF as solvent.
Compound 50: 3-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl] benzamide.
] This compound is prepared via general method E using intermediate 11 and 5-carbamoyl fluorobenzeneboronic acid, with CsF as base and DMF as solvent.
Compound 51: 3-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl] fluoro-benzamide.
This compound is prepared via general method E using intermediate 11 and 3-(aminocarbonyl) fluorobenzeneboronic acid, with CsF as base and DMF as solvent. nd 52: 9 -(3 ,3 -Dimethyl-butynyl)([1,4]dioxanylmethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone.
This compound is prepared via l method G using ediate 11 and 3,3-dimethyl-but yne.
Compound 53: 2-([1,4]dioxanylmethoxy)-9 -pyridinylethynyl-6,7 -dihydro-pyrimido [6,1 -a]isoquinolin- 4-one.
This compound is prepared via general method G using intermediate 11 and 4-ethynyl-pyridine. nd 54: 2-([1,4]di0xanylmeth0xy)(3 -methyl-is0xazol-5 -ylmeth0xy)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quin01in0ne.
This compound is prepared Via general method F using ediate 8 and 5-chlor0methyl methyl-isoxazole.
Compound 55: 2-([1,4]di0xanylmeth0xy)—9-(3 xy-3 -methyl-but-1 -ynyl)-6 ,7 -dihydr0-pyrimid0 [6 ,1 - a]is0quin01in0ne.
This compound is prepared Via general method G using intermediate 11 and 2-methyl—butyn Compound 56: 2-([1 ,4]di0xanylmeth0xy)(2-meth0xy—pyridin-3 ,7 -dihydr0-pyrimid0[6,1 - a]is0quin01in0ne.
This compound is prepared Via l method E using intermediate 11 and 2-meth0xy pyridinyl boronic acid.
Compound 57 : 2-([1,4]di0xanylmeth0xy)-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
This compound is prepared Via general method E using intermediate 11 and ium (cyanomethyl) trifluoroborate.
Compound 58: 9 -(3 ,6-dihydr0-2H-pyranyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 3,6-dihydro-2H- pyranb0r0nic acid pinacol ester. nd 59: 5-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]- pyridine-Z-carb onitrile.
This compound is prepared Via general method E using intermediate 11 and 2-cyan0pyridine boronic acid pinacol ester.
Compound 60: 4]Di0xanylmeth0xy)(6-is0pr0p0xy—pyridinyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 6- isopropoxypyridineb0r0nicacid pinacol ester.
Compound 61: 2-([1,4]di0xanylmeth0xy)-9 -(6-eth0xy—pyridin-3 -yl)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 6-eth0xypyridine boronic acid. nd 62: 2-([1,4]di0xanylmeth0xy)(6-m0rpholinyl-pyridinyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 4,4,5,5- tetramethyl-1 ,3 ,2-di0xab0rolanyl)pyridinyl]m0rpholine.
Compound 63: 9-(2,3 -dimeth0xy—phenyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quin01in0ne.
This nd is prepared Via general method E using intermediate 11 and 2,3- dimethoxyphenylboronic acid.
Compound 64: 9-(3-chlor0meth0xy—pyridinyl)([1,4]di0xanylmeth0xy)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This nd is prepared Via general method E using intermediate 11 and r0 methoxypyridineb0r0nic acid.
Compound 65: 4]di0xanylmeth0xy)-9 -(2-methyl-pyridinyl)-6,7 r0-pyrimid0 [6,1 - a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 2-methylpyridine boronic acid pinacol ester. nd 66: 3-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]- isonicotinonitrile.
This compound is prepared Via general method E using intermediate 11 and 4-cyan0pyridine boronic acid pinacol ester.
Compound 67 : 9-(2,5 -dimeth0xy—phenyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 2,5- dimethoxyphenylboronic acid.
Compound 68: 2-([1,4]dioxanylmethoxy)(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-6,7-dihydropyrimido [6,1 -a]isoquinolinone.
This compound is ed Via general method E using intermediate 11 and 1-[5-(4,4,5,5- tetramethyl-1 ,3 ,2-dioxaborolanyl)pyridinyl]piperidine.
Compound 69: 2-([1,4]dioxanylmethoxy)-9 -(2-ethoxy—pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 - uinolinone.
] This compound is prepared Via general method E using intermediate 11 and 2-ethoxypyridine boronic acid.
Compound 70: 9-(2 ,6 -dimethoxy—pyridinyl)([ 1 ,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
] This compound is prepared Via general method E using intermediate 11 and 2,6-dimethoxy pyridineboronic acid.
Compound 71: 4-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]- nicotinonitrile.
This compound is ed Via l method E using intermediate 11 and 3-cyanopyridine boronic acid, pinacol ester.
Compound 72: 9-tert-butoxymethyl([1,4]dioxan-Z-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
This compound is prepared Via general method E using intermediate 11 and potassium tert- butoxymethyltrifluoroborate.
Compound 73: 2-([1,4]dioxanylmethoxy)(2-pyrrolidinyl-pyridinyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared Via general method E using intermediate 11 and rolidinyl) (4,4,5 ,5 -tetramethyl- 1 ,3 ,2 -dioxab orolan-2 ridine.
Compound 74: 2-([1,4]dioxanylmethoxy)(6-pyrrolidinyl-pyridinyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared Via general method E using intermediate 11 and 2-(1-pyrrolidinyl) (4,4,5 ,5 -tetramethyl- 1 ,3 ,2 -dioxab orolan-2 -yl)pyridine.
Compound 75: 2-([1,4]di0xanylmeth0xy)(5-phenyl-0xazolylmeth0xy)-6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne.
This compound is prepared Via general method F using intermediate 8 and 2-chlor0methyl phenyl-oxazole.
Compound 76: 9-(5-tert-butyl-0xaz01—2-ylmeth0xy)—2-([1,4]dioxan-Z-ylmethoxy)-6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne.
This compound is prepared Via l method F using intermediate 8 and 5-tert-butyl chloromethyl-oxazole.
Compound 77: 9-(5-cyclopr0pyl-[1,2,4]0xadiazolylmeth0xy)—2-([1 ,4]di0xanylmeth0xy)-6,7-dihydr0- pyrimido [6,1 quinolin0ne.
This nd is prepared Via general method F using intermediate 8 and 3-chlor0methyl cyclopropyl— [ 1 ,2,4] oxadiazole.
Compound 78: 2-([1,4]di0xanylmeth0xy)-9 -(5 -ethyl-[1,2,4]0xadiazol-3 h0xy)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 8 and 3-chlor0methyl ethyl-[1,2,4]0xadiazole.
Compound 79: 2-([1,4]di0xanylmeth0xy)-9 -(5 -methyl-[1,2,4]0xadiazol-3 -ylmeth0xy)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 8 and 3-chlor0methyl methyl-[1,2,4]0xadiazole.
Compound 80: 2-([1 ,4]di0xanylmeth0xy)-9 -(5 0pyl—[1,2,4]0xadiazol-3 h0xy)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 8 and 3-chlor0methyl isopropyl- [ 1 ,2,4] zole.
Compound 81: 9-cyclopentylethynyl([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -a]is0quinolin- 4-0ne.
This compound is ed Via general method G using intermediate 11 and ethynyl- cyclopentane.
Compound 82: 9 -cyclohexylethynyl([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimid0 [6,1 -a]isoquinolin- 4-one.
This compound is prepared via general method G using intermediate 11 and ethynyl-cyclohexane.
Compound 83: 2-( [1 ,4 ]di0xanylmeth0xy)-9 -(3 -methyl-but-1 -ynyl) -6 ,7 -dihydr0-pyrimid0 [6 ,1 - a]isoquinolin0ne.
] This compound is prepared via general method G using intermediate 11 and 3-methyl-butyne.
Compound 84: 2-([1 ,4]di0xanylmeth0xy)hex-1 -ynyl-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
[00344] This compound is prepared via general method G using intermediate 11 and hex-1 -yne.
Compound 85: 9- [3 -(benzyl-methyl-amin0)-pr0pynyl]([1 ,4]di0xanylmeth0xy)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared via general method G using intermediate 11 and benzyl—methyl—prop- 2-ynyl-amine.
Compound 86: 2-([1,4]di0xanylmeth0xy)(3-hydr0xy-5 -methyl-hex-1 -ynyl)-6,7 r0-pyrimid0[6,1 - a]isoquinolin0ne.
] This compound is prepared via general method G using intermediate 11 and 5-methyl-hexyn 01, with lPerH as base and THF as t.
Compound 87 : 2-([1,4]dioxanylmeth0xy)-9 -(3 -hydr0xy-but-1 -ynyl)-6,7 -dihydr0-pyrimid0 [6,1 - a]isoquinolin0ne.
This compound is prepared via general method G using ediate 11 and ynol, with iPrZNH as base and THF as solvent.
Compound 88: 9-cyclopr0pyl—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimid0 [6,1 quinolinone.
This compound is prepared via general method E using intermediate 11 and potassium cyclopropyltrifluoroborate.
Compound 89: 2-([1 xanylmeth0xy)(3 xy—pent-1 -ynyl)-6,7 -dihydr0-pyrimid0 [6,1 - a]isoquinolin0ne.
This compound is prepared via general method G using intermediate 11 and pentynol with iPrZNH as base and THF as solvent.
Compound 90: 2-([1,4]Di0xanylmeth0xy)—9-(3 -hydr0xy—4-methyl-pent-1 -ynyl)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared via general method G using intermediate 11 and 4-methyl-pentyn- 3-01 with iPrZNH as base and THF as t.
Compound 91: 2-([1,4]dioxan-Z-ylmethoxy)(3 -ethylhydr0xy—pentynyl)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared via general method G using intermediate 11 and 3-ethyl-pentyn 01 with iPrZNH as base and THF as t.
Compound 92: 2-([1,4]dioxan-Z-ylmethoxy)(3-hydr0xy—3-phenyl-butynyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne.
This compound is prepared via l method G using intermediate 11 and 2-phenyl—butyn 01 with Cs2C03 as base and MeCN as solvent under reflux.
Compound 93: 9-(3 -benzylamin0-pr0pynyl)([1,4]di0xanylmeth0xy)-6,7 -dihydr0-pyrimid0 [6,1 - uinolin0ne.
This nd is prepared via general method G using intermediate 11 and benzyl-prop-Z-ynylamine with Cs2C03 as base and MeCN as solvent under reflux.
Compound 94: 2-([1,4]di0xanylmeth0xy)[(furan-Z-ylmethyl)-amin0]-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne.
ON ON ° 5° 0 O O N O N OTf Nmm Intermediate 11 Compound 94 A suspension of intermediate 11 (200 mg, 0.433 mol, 1 eq.), fiJran-Z-ylmethanamine (0.038 mL, 0.433 mol, 1 eq.) and Cs2C03 (0.17g, 0.519 mmol, 1.2 eq.) in toluene (4 mL) was degassed with Ar for 30 min before BINAP (+/—) (16 mg, 0.026 mmol, 0.06 eq.) and )2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added. The reaction was heated to 65 °C for 16 h. The reaction was cooled to RT, BINAP (+/—) (16 mg, 0.026 mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added and the reaction was degassed.
The on was heated to 80 °C for 1 extra day. The reaction was cooled to RT, BINAP (+/—) (16 mg, 0.026 mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added and the on was degassed.
The reaction was heated to 80 °C for 1 extra day. The reaction was cooled to RT and diluted with DCM and washed with 0.5N aqueous KHSO4. The aqueous layer was extracted with DCM, the combined organic layers were dried over Na2S04 and evaporated to dryness. The crude product was purified by preparative HPLC-MS [H20 (9892): MeCN (29 98) / 0.1%HC02H] to give compound 94.
(H, CDC13) 5 ppm 7.57 - 7.48 (1 H, d), 7.38 (1 H, s), 6.68 - 6.55 (1 H, d), 6.49 (1 H, s), 6.35 (1 H, s), 6.28 (1 H, s), 6.20 (1 H, s), 4.60 - 4.50 (1 H, m), 4.38 - 4.30 (4 H, m), 4.22 - 4.15 (2 H, m), 4.03 - 3.93 (1 H, m), 3.95 - 3.60 (5 H, m), 3.55 -3.40 (1 H, t), 2.98 - 2.85 (2 H, m) MW (calcd): 409.4; MW (obsd): 410.2 (M+1) Compound 95: 2-([1,4]dioxanylmethoxy)-9 -(1-ethyl-1H-pyrazolyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This compound is prepared via general method E using intermediate 11 and 1-ethyl-1H-pyrazole- 4-boronic acid, pinacol ester.
Compound 96: 4]dioxanylmethoxy)-9 -[1-(3 -methyl-butyl)-1H-pyrazolyl]-6,7-dihydropyrimido [6,1 -a]isoquinolinone.
] This compound is prepared via l method E using intermediate 11 and 1-(3-methylbutyl)- 1H-pyrazoleboronic acid, pinacol ester.
Compound 97: 2-([1,4]dioxanylmethoxy)-9 -(5 -methyl-furanyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This compound is prepared via l method E using intermediate 11 and 2-methylfurane boronic acid pinacol ester. nd 98: 2-([1,4]dioxanylmethoxy)-9 -(3 -hydroxy-hex-1 -ynyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This compound is prepared via general method G using intermediate 11 and hexynol, Cs2C03 as base and MeCN as solvent under reflux.
Compound 99: 9-(3 ,5 -dimethyl-1H-pyrazolyl)—2-([1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 - uinolinone.
This compound is prepared via general method E using intermediate 11 and 3,5 -dimethylpyrazole- 4-boronic acid pinacol ester.
Compound 100: 2-([1,4]di0xanylmeth0xy)(1H-pyrazol—4-yl)-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin- 4-one.
This compound is ed Via general method E using intermediate 11 and pyrazoleb0r0nic acid l ester.
Compound 101: 2-([1,4]dioxan-Z-ylmethoxy)(1-pr0pyl-1H-pyrazolyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne.
] This compound is prepared Via general method E using intermediate 11 and l-propyl-lH- pyrazoleboronic acid, pinacol ester.
Compound 102: 2-[2-((R)[1,4]di0xanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin yl]-benz0nitrile.
This compound is prepared Via general method E using intermediate 10 and 2- cyanophenylboronic acid l ester.
Compound 103: 2-[2-((S)[1,4]di0xanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin yl]-benz0nitrile.
This compound is prepared Via general method E using intermediate 9 and 2-cyan0phenylb0r0nic acid pinacol ester.
Compound 104: 9-(5 propyl-[1,2,4]0xadiazol—3 hoxy)—2-((R)[1,4]dioxan-Z-ylmethoxy)-6,7 - dihydro-pyrimid0[6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 7 and 3-chlor0methyl cyclopropyl— [ 1 ,2,4] oxadiazole.
Compound 105: 2-([1,4]dioxan-Z-ylmethoxy)—9-ethynyl-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne. o/fio o 0/} 0 O 0 Step 1 Step 2 N / ———> N / ———> N / 0%N I I I O N O N OTf § % SiMe3 Intermediate 11 Intermediate 24 Compound 105 Step I .' 2-([I,4]dt0xanylmeth0xy)pr0p-I 6, 7—dihydr0-pyrtmtdo[6, I -a]t's0quinoltn0ne (Intermediate 24).
Intermediate 24 2-([1,4]dioxanylmethoxy)propynyl-6,7-dihydro-pyrimido[6,1- a]isoquinolinone is synthesised via general method E with intermediate 11 and ethynyl-trimethyl-silane. (1H, CDC13) 5 ppm 7.66 - 7.61 (1 H, m), 7.47 - 7.43 (1 H, m), 7.42 - 7.38 (1 H, m), 6.37 (1 H, s), 4.50 - 4.36 (2 H, m), 4.23 — 3.93 (1 H, m), 3.90 — 2.97 (1 - 4.16 (2 H, m), 4.04 - 3.60 (4 H, m), 3.53 - 3.44 (1 H, m), 3.02 H, m), 0.27 (7 H, s) MW ): 410.5; MW (obsd): 411.4 (M+1) Step 2: 2-([I ,4]dt0xanylmeth0xy)ethynyl—6, dr0-pyrtmtdo[6,1 -a]tsoqutnolin-4—0ne (Compound I 05).
TBAF (4.06 mL, 4.06 mmol, 1.2 eq.) was added dropwise to a solution of intermediate 24 (1.39 g, 3.39 mmol, 1 eq.) in THF (40 mL) at 0 °C and the on was stirred for 1 h at 0 °C. The reaction was then evaporated to dryness, and the residue was re-dissolved in HCl 1N. The aqueous phase was extracted with DCM, the combined organic layers were dried over MgSO4 and the solvent evaporated under vacuum. The crude product was ed by flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM to furnish compound 105.
(H, CDC13) 6 ppm 7.65 (1 H, s), 7.51 - 7.46 (1 H, m), 7.45 - 7.41 (1 H, m), 6.37 (1 H, s), 4.49 - 4.36 (2 H, m), 4.21 (2 H, s), 4.04 — 3.94 (1 H, m), 3.90 - 3.61 (5 H, m), 3.53 - 3.44 (1 H, m), 3.25 (1 H, s), 3.00 (2 H, s) MW ): 330.3; MW (obsd): 331 Compound 106: 2-([1 ,4]dioxanylmethoxy)pyrimidinylethynyl-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
I —> O N Compound 105 Compound 106
[00368] Compound 105 (50 mg, 0.15 mol, 1 eq.) was dissolved in DMF (3 mL), 5-bromo-pyrimidine (47 mg, 0.30 mmol, 2 eq.) was added followed by TEA (0.062 mL, 0.44 mmol, 3 eq.), and the mixture was degassed. Pd(PPh3)3C12 (5 mg, 0.0074 mmol, 0.05 eq.) was added with CuI (6 mg, 0.029 mmol, 0.2 eq.) and the reaction mixture was heated at 80 °C for 16 h. The volatiles were evaporated to dryness and the crude product was purified by flash tography on silica gel, eluting from 0 to 5% MeOH/DCM to give compound 106.
Compound 107 : 2-([1,4]dioxanylmethoxy)(3-phenylamino-propynyl)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
This nd is prepared via general method G using intermediate 11 and phenyl-propynylamine with iPrZNH as base and THF as solvent.
Compound 108: 2-([1,4]dioxanylmethoxy)-9 -(3 -hydroxy—3 -pyridin-3 -yl-prop-1 -ynyl)-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
This nd is ed via general method G using intermediate 1 1 and 1 -pyridin-3 -yl-prop- 2-yn01.
Compound 109: 9 -cyclopentyloxymethyl—2-([ 1 ,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 - uinolinone.
This compound is prepared via general method E using intermediate 11 and potassium cyclopentoxymethyltrifluoroborate.
Compound 1 1 0: 2-([1,4]dioxanylmethoxy)—9-(3 -methoxymethyl-pentynyl)-6,7-dihydro- pyrimido [6 ,1 -a]isoquinolinone.
Synthesis fiJlly described above.
Compound 1 1 1: 9-cyclopropylethynyl—2-((R)-1 -[1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimido [6,1 - uinolinone.
This compound is prepared via general method G using intermediate 10 and ethynyl- cyclopropane.
Compound 1 12: 2-((S)[1,4]dioxanylmethoxy)(3 -methyl-butynyl)-6,7 -dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared via general method G using intermediate 9 and 3-methyl-butyne.
Compound 1 13: 2-([1 ,4]Dioxanylmethoxy)-9 -(3 -imidazol-1 -yl-prop-1 -ynyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This compound is prepared via general method G using intermediate 11 and 1-propynyl-1H- imidazole.
Compound 1 14: 9-(2-cyclopropyl-ethyl)((R)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
O/fi o/fi 3" O O I i’ I O N O N ediate 10 Compound 114 A round bottom flask was charged with intermediate 10 (2 g, 4.33 mol, 1 eq.), intermediate 20 (1.1 g, 6.5 mmol, 1.5 eq.), K2CO3 (1.8 g, 13 mol, 3 eq.), Pd(OAc)2 (19 mg, 0.087 mmol, 0.02 eq.), RuPhos (81 mg, 0.173 mmol, 0.04 eq.), toluene (30 mL) and H20 (3 mL). The mixture was degassed with N2 and was heated at 80 °C for 16 h. The reaction was cooled to RT, ed with brine and extracted with EtOAc. The organic layer was dried over MgSO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 70 to 90% EtOAc/H to give compound 114.
(H, CDC13) 8 ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.25 — 3.95 (1 H, m), 3.90 — 2.95 (2 H, - 4.17 (2 H, m), 4.03 - 3.61 (5 H, m), 3.54 - 3.45 (1 H, m), 3.02 m), 2.81 - 2.72 (2 H, m), 1.59 - 1.49 (2 H, m), 0.77 - 0.64 (1 H, m), 0.49 - 0.42 (2 H, m), 0.10 - 0.02 (2 H, m) MW (calcd): 382.5; MW (obsd): 383.4 (M+1) Compound 115: 9-cyclopentyloxymethyl((R)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
[00377] This nd is prepared via general method E using intermediate 10 and potassium cyclopentoxymethyltrifluoroborate.
Compound 116: 2-([1,4]dioxanylmethoxy)(3 -hydroxypyridinyl-propyl)-6,7-dihydropyrimido [6 ,1 -a]isoquinolinone.
[00378] Synthesis fiJlly bed above.
Compound 1 17 : 9 oxy((R)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolin one. sis fiJlly described above. 2012/076275 Compound 1 18: 9-allyloxy—2-((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin one.
Synthesis fiJlly described above.
Compound 1 19: 2-((R)[1 ,4]dioxanylmethoxy)(tetrahydro-pyranyloxymethyl)-6,7-dihydro- pyrimido [6,1 quinolinone.
This compound is prepared via general method E using intermediate 10 and intermediate 14.
Compound 120: 2-([1 ,4]dioxan-Z-ylmethoxy)—9- {3 -[(pyridin-3 -ylmethyl)-amino]-propynyl}-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
] This compound is ed via general method G using intermediate 11 and prop-Z-yn-l- yl(pyridinylmethyl)amine.
Compound 12 1: 2-((R)[1,4]dioxan-Z-ylmethoxy)—9-pentyl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
This Compound is prepared via general method I using compound 111.
Compound 122: 9-cyclopropylethynyl—2-((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
[00384] Intermediate 9 (13.5 g, 29.20 mmol, 1 eq.) was dissolved in degassed DMF (1000 mL) under an nitrogen atmosphere, ethynyl cyclopropane (3.5 g, 53.00 mmol, 1.8 eq.) was added followed by Pd(PPh3)3C12 (1.11 g, 1.58 mmol, 0.05 eq.), CuI (1.9 g, 9.98 mmol, 0.34 eq.) and TEA (12.5 mL, 89.7 mmol, 3.1 eq.). The reaction mixture was stirred 3h at 80 °C and 15 h at room temperature. The reaction was concentrated under vacuum. The crude product was then purified by ation in hot iPrOH to afford compound 122. ] (1H, CDC13) 5 ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H, s), 4.50 - 4.39 (2 H, m), 4.20 (2 H, t), 4.02 - 3.98 (1 H, m), 3.89 - 3.66 (5 H, m), 3.49 (1 H, t), 2.96 (2 H, t), 1.59 - 1.48 (1 H, m), 0.98 - 0.81 (4 H, m) MW (calcd): 378.4; MW (obsd): 379.4 ee = 98.3% WO 92791 Compound 123: 9 -(2-cyclopropyl-ethyl)((S) [1 ,4]dioxanylmethoxy)—6,7-dihydropyrimido [6,1 - a]isoquinolinone.
O O i" —» Na 0 N CAN Intermediate 9 Compound 123 A round bottom flask was charged with intermediate 9 (2.08 g, 4.51 mol, 1 eq.), intermediate 20 (1.35 g, 7.67 mmol, 1.7 eq.), K2CO3 (1.87 g, 13.53 mol, 3 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.02 eq.), RuPhos (84 mg, 0.18 mmol, 0.04 eq.), toluene (30 mL) and H20 (3 mL). The mixture was degassed with N2 and was heated at 80 °C for 1.5 days. The reaction was cooled to RT and some more reagents were added, potassium 2-cyclopropyl-ethyl-trifluoroborate (0.3 eq.), Pd(OAc)2 (0.02 eq.), RuPhos (0.04 eq.), the reaction was degassed and the reaction was heated at 80 °C for 16h. The reaction was cooled to RT, quenched with H20 and extracted with EtOAc. The organic layer was dried over MgSO4 and ated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 80 to 90% EtOAc/H to compound 123.
(H, CDC13) 6 ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.24 — 3.95 (1 H, m), 3.91 — 2.95 (2 H, m), 2.81 - 4.17 (2 H, m), 4.03 - 3.62 (5 H, m), 3.49 (1 H, dd), 3.03 - 2.73 (2 H, m), 1.59 - 1.50 (2 H, m), 0.71 (1 H, s), 0.49 - 0.42 (2 H, m), 0.09 - 0.03 (2 H, m) MW (calcd): 382.5; MW : 383.4 Compound 124: 2-((S)[1 ,4]dioxanylmethoxy)-9 -(oxetan-3 -yloxymethyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
[00387] This nd is ed Via general method E using intermediate 9 and intermediate 15.
Compound 125: 2-((S)[1,4]dioxanylmethoxy)(3 l-oxetan-3 -ylmethoxymethyl)-6,7-dihydro- do [6,1 -a]isoquinolinone.
This compound is prepared Via general method E using intermediate 9 and intermediate 16.
Compound 126: 9-(2,2-dimethyl-butylamino)—2-((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
Synthesis fiJlly described above.
Compound 127 : 2-((S)[1,4]di0xanylmeth0xy)(3-hydr0xymethyl-pentyl)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne. o 0/} 0 $0 0 _ $0 0/ o/ 0/- SteP 1 Step 2 N , N , N / DAN | DAN | CAN I OTf Q Intermediate 9 Intermediate 25 Compound 127 Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)(3-hydr0xymethyl—pent—I -ynyl)-6, 7—dt'hydr0-pyrt'mtd0[6,1 - utnolin0ne (Intermediate 25) Intermediate 25 is prepared Via general method G using intermediate 9, 4-Methyl-pentynol, tPrZNH as base and THF as solvent. (1H, CDC13) 5 ppm 7.65 - 7.60 (1 H, d), 7.48 - 7.40 (1 H, m), 7.37 (1 H, s), 6.36 (1 H, s), 4.50 - 4.30 (3 H, m), 4.25 - 4.15 (2 H, m), 4.05 - 3.95 (1 H, m), 3.92 - 3.60 (6 H, m), 3.68 - 3.40 (1 H, m), 3.05 - 2.92 (2 H, m), 2.10 - 1.95 (1 H, m), 1.93 - 1.80 (1 H, m), 1.15 - 1.00 (6 H, m) MW (calcd): 410.5; MW (obsd): 411.2 (M+1) Step 2 .' 2-((S)-I -[I , 4]dioxan-Z-ylmethoxy) (3-hydr0xy-4—methyl—pentyl)-6, 7—dthydr0-pyrtmtd0[6, I - utnolin0ne und 12 7)
[00391] Compound 127 is prepared Via general method I using intermediate 25.
Compound 128: 2-((S)[1,4]di0xanylmeth0xy)(2-ethyl—hexylamin0)-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne.
This nd is prepared Via general method J using intermediate 13 and 2-ethyl-hexanal.
Compound 129: 2-((S)—1-[1,4]di0xanylmeth0xy)(2-meth0xy-eth0xy)-6,7-dihydr0-pyrimid0[6,1- a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 6 and 1-bromomethoxy- , KI was not used in this experiment.
Compound 130: 2-((S)-1 - [1 ,4 ]di0xanylmeth0xy)-9 -(2-eth0xy-eth0xy)-6 ,7 -dihydr0-pyrimid0 [6 ,1 - a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 6 and 1-bromoethoxy- ethane, K1 was not used in this experiment.
Compound 131: 9-cyclopropylmethoxy((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
This compound is prepared Via general method F using intermediate 6 and bromomethyl- cyclopropane, K1 was not used in this ment.
Compound 132: 2-((S)[1,4]dioxanylmethoxy)(2-fluoro-ethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared Via general method F using intermediate 6 and 1-bromofluoro- ethane, K1 was not used in this experiment.
Compound 133: 2-((S) [1 ,4]dioxanylmethoxy) [3 -(2-methoxy-ethoxy)-propynyl]-6,7-dihydro- do [6,1 -a]isoquinolinone.
Synthesis fiJlly bed above.
Compound 134: 2-((S)[1,4]dioxanylmethoxy)[3-(2-ethoxy-ethoxy)-propynyl]-6,7-dihydropyrimido [6,1 -a]isoquinolinone.
[00398] This compound is prepared Via general method K using intermediate 21 and 1-bromoethoxy- ethane.
Compound 135: [1 ,4]dioxanylmethoxy) [3 -(2-fluoro-ethoxy)-propynyl]-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
[00399] This compound is prepared Via general method K using intermediate 21 and 1-bromofluoro- ethane.
Compound 136: 9 -(2,2-dimethyl-propoxymethyl)((S) [1 ,4]dioxanylmethoxy)-6,7-dihydro- do [6,1 -a]isoquinolinone.
[00400] This compound is prepared Via general method E using ediate 9, in a mixture of DME/HZO (2/1), in a ave at 120 °C for 20 min and intermediate 17.
Compound 137: ohexyloxymethyl—2-((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
WO 92791 This compound is prepared Via general method E using intermediate 9 and potassium cyclohexyloxymethyltrifluoroborate in a mixture of DME/HZO (2/ 1), in a ave at 120 °C for 20 min.
Compound 138: 9-cyclopropylmethoxymethyl-Z-((S) [1 ,4]dioxanylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
This compound is prepared Via general method E using intermediate 9, in a e of DME/HZO (2/ 1), in a microwave at 120 °C for 20 min and intermediate 18.
Compound 139: 2-((S)[1 ,4]dioxanylmethoxy)(tetrahydro-pyranylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
This compound is prepared Via general method F using intermediate 6 and 2-bromomethyl- tetrahydro-pyran, KI was not used in this experiment. nd 140: 2-((S) [1 ,4 ]dioxanylmethoxy)-9 -(3 -hydroxy-butyl)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone. 07)K/ OKE/o 05/0 0 0 O Step 1 Step 2 O N 0%N 0%N OTf § Intermediate 9 Intermediate 26 Compound 140 Step I .' 2-((S)-I -[I,4]Dt0xanylmeth0xy)-9—(3-hydr0xy-but—I -ynyl)-6, 7-dihydr0-pyrtmtd0[6,1 - a]isoquinolin0ne (Intermediate 26). ediate 26 was prepared Via general method G using intermediate 9 and but-3 -ynol, the crude product was used in the next step without characterization.
Step 2: -I -[I,4]dt0xanylmeth0xy)(3-hydr0xy-butyl)-6, 7-dihydr0-pyrimtd0[6,1 -a]ts0quinoltn0ne (Compound 140).
] Compound 140 was prepared Via general method I using intermediate 26.
Compound 141: 9-(4,4-dimethy1-penty10xy)—2-((S)-1 -[1,4]di0xany1meth0xy)-6,7-dihydr0-pyrimid0[6,1 - a]is0quin01in0ne.
O O I| | O N —> j: O N OH OW Intermediate 6 Compound 141 Intermediate 6 (0.1 g, 0.303 mol, 1 eq.), 4,4-dimethy1—pentan01 (35 mg, 0.303 mmol, 1 eq.) and PPh3 (95 mg, 0.363 mmol, 1.2 eq.) were suspended in 1,4-di0xane (5 mL) and the mixture was degassed with N2. DIAD (0.065 mL, 0.333 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by preparative TLC eluting with EtOAc to give compound 141.
(H, CDC13) 5 ppm 7.70 - 7.58 (1 H, d), 6.95 - 6.82 ( 1 H, d), 6.77 (1 H, s), 6.27 (1 H, s), 4.50 - 4.32 (2 H, m), 4.38- 4.15 (2 H, m), 4.05 - 3.92 (3 H, m), 3.92 - 3.60 (5 H, m), 3.55 - 3.42 (1 H, t), 3.05 - 2.92 (2 H, m), 1.85 - 1.70 (2 H, m), 1.40 - 1.30 (2 H, m), 0.92 (9 H, s) MW (calcd): 428.5; MW (obsd): 429.2 (M+1) Compound 142: 2-((S)[1,4]di0xany1meth0xy)(3-meth0xymethy1-penty1)-6,7-dihydr0- do [6,1 -a]is0quin01in0ne.
O O O b0 b0 b0 O/ O/ 0’- Step 1 Step 2 N / _ ,.
OAN I 31/ _ I i/ I O N O N % Q OH 0\ Intermediate 25 Intermediate 27 Compound 142 Step I .' 2-((S)-I -[I ,4]Dt0xanylmeth0xy)(3-meth0xymethyl—pent—I -ynyl)-6, dr0-pyrtmtd0[6,1 - ajtsoqutnoltn0ne (Intermediate 2 7)
[00407] Intermediate 27 is prepared via general method H using intermediate 25.
MW ): 424.5; MW (obsd): 425.2 (M+1) Step 2: -I -[1,4]dioxan-Z-ylmethoxy)-9— (3-melh0xy-4—melhyl—penlyl)-6, 7-dihydr0-pyrimid0[6, I - a]isoquinolin0ne (Compound 142).
] Compound 142 is prepared Via general method I using intermediate 27.
Compound 143: 9-(3-cyclopropyl-propoxy)((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
OQ OQ 0} O} N / N / 0*N I I —’ 0%N OH 0% Intermediate 6 nd 143 Intermediate 6 (2.12 g, 2.42 mol, 1 eq.), 4,4-dimethyl-pentanol (0.77 g, 7.71 mmol, 1.2 eq.) and PPh3 (2.02 g, 7.71 mmol, 1.2 eq.) were suspended in 1,4-dioxane (50 mL) and the mixture was degassed with N2. DIAD (1.56 mL, 7.71 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h.
The reaction mixture was quenched with brine and extracted with EtOAc, the organic phase was dried over MgSO4 and ated to dryness. Compound 143 was obtained by purification by flash chromatography on silica gel, eluting from 60 to 100% EtOAc/H. (1H, CDC13) 5 ppm 7.66 - 7.60 (1 H, m), 6.91 - 6.86 (1 H, m), 6.80 - 6.76 (1 H, m), 6.28 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 — 3.95 (1 H, m), 3.91 - 4.17 (2 H, m), 4.11 - 4.04 (2 H, m), 4.02 - 3.61 (5 H, m), 3.54 - 3.45 (1 H, m), 3.03 — 2.94 (2 H, m), 1.98 - 1.88 (2 H, m), 1.45 - 1.36 (2 H, m), 0.78 - 0.66 (1 H, m), 0.50 - 0.43 (2 H, m), 0.09 - 0.03 (2 H, m) MW (calcd): 412.5; MW (obsd): 413.5 Compound 145: 9-cyclohexylamino((S)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
This compound is ed Via general method J using intermediate 13 and cyclohexanone.
Compound 146: 2-((S)[1,4]dioxanylmethoxy)—9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydropyrimido [6,1 -a]isoquinolinone. $0 $0 o O/E /E O 0/5 Step 1 Step 2 0%N 0%N 0%N OTf § Intermediate 9. Intermediate 28 Compound 146 Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)(3-hydr0xy-4,4-dt'methyl—pent—I -ynyl)-6, 7-dt'hydr0- pyrtmtd0[6,1 -a]is0qutnoltn0ne (Intermediate 28).
Intermediate 28 is prepared Via l method G using intermediate 9.
MW (calcd): 424.5; MW (obsd): 425.4 (M+1) Step 2: 2-((S)-I -[I ,4]dioxan-Z-ylmethoxy)(3-hydr0xy-4, thyl—pentyD-6, 7-dt'hydr0-pyrt'mt'd0[6,1 - a]isoquinolin0ne (Compound 146).
Compound 146 is prepared Via general method I using intermediate 28.
Compound 147: opentylmethoxymethyl-Z-((S) [1 ,4]dioxanylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolinone.
This compound is ed Via general method E using intermediate 9, in a mixture of DME/HZO (2/ 1), in a microwave at 120 °C for 20 min and intermediate 19.
C0mpound 148: 2-((S)[1,4]dioxanylmethoxy)—9-(3 -methoxy—butyl)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone.
(La/O 0/} 0/} Ké/o 5/0 0 O 0 Step 1 Step 2 j: —' N —' N I | | | O N CAN CAN % % OH 0\ ediate 26 Intermediate 29 Compound 148 Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)-9—(3-meth0xy-but—I -ynyl)-6, 7-dt'hydr0-pyrt'mt'd0[6,1 - a]isoquinolin0ne (Intermediate 29) ediate 29 is prepared Via general method H using intermediate 26.
MW ): 396.4; MW (obsd): 397.2 (M+1) Step I .' 2-((S)-I -[I ,4]dioxan-Z-ylmethoxy)(3-methoxy-butyl)-6, 7-dthydro-pyrt'mtdo[6,1 -a]isoqutnoltn one (Compound 148) Compound 148 is prepared Via general method I using intermediate 29.
Compound 149: [1 ,4]dioxanylmethoxy)(3 lamino-propyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone O O O K/O K/O K/O ; ; ; 0 0 O Step 1 Step 2 N / —, N / —, N / 0%N I 0%N I 0%N I OTf § H N \© Intermediate 9 Intermediate 30 Compound 149 Step I .' -I -[I,4]Dtoxanylmethoxy)-9—(3-phenylamt'no-prop-I -ynyl)-6, 7-dthydro-pyrt'mtdo[6,1 - a]isoquinoltnone (Intermediate 30) Intermediate 30 is prepared Via general method G using intermediate 9 and phenyl-prop-Z-ynyl- amine.
MW (calcd): 443.5; MW (obsd): 444.2 (M+1) Step 2: 2-((S)-I -[I , 4]dioxan-Z-ylmethoxy)(3-phenylamtno-propyl)-6, 7-dthydro-pyrt'mtdo[6,1 - a]isoquinoltnone (Compound 149) Compound 149 is prepared Via general method I using intermediate 30.
Compound 150: -1 -[1,4]dioxanylmethoxy)(4-hydroxy-pentyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone. moK/ (LE/o (Li/o O O 0 Step 1 Step 2 CAN CAN o//I\N OH OTf § Intermediate 9 Intermediate 31 Compound 150 Step I .' 2-((S)-I -[I ,4]Dt'oxanylmetnoxy)(4—hydroxy-pent—I -ynyl)-6, 7—dt'nydro-pyrt'mt'do[6,1 - a]isoquinolinone (Intermediate 3]) Intermediate 31 was prepared Via general method G using intermediate 9, -ynol, iPrZNH as base and THF as solvent.
MW (calcd): 396.4; MW (obsd): 397.2 (M+1) Step 2: 2-((S)-I -[I ,4]dt'oxanylmetnoxy)(4—hydroxy-pentyl)-6, 7—dt'nydro-pyrt'mt'do[6,1 -a]t'soqut'nolt'n one (Compound 150)
[00419] nd 150 was prepared Via general method I using ediate 31.
Compound 151: 2-((S)[1 ,4]dioxanylmethoxy)(4-hydroxy-butyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone. o 0/} 0 $0 0 _ $0 0,: 0,: ,2 Step 1 Step 2 Oék N O N O N OTf Q OH Intermediate 9 Intermediate 32 Compound 151 Step I .' 2-((S)-I -[I,4]Dtoxanylmetnoxy)(4—hydroxy-but—I -6, 7-dt'nydro-pyrt'mt'do[6,1 - a]isoquinolinone (Intermediate 32) Intermediate 32 was prepared Via general method G using intermediate 9, but-3 -ynol, iPrZNH as base and THF as t. (1H, CDC13) 8 ppm 7.70 - 7.65 (1 H, m), 7.45 - 7.35 (1 H, m), 7.34 (1 H, s), 6.35 (1 H, s), 4.50 - 4.32 (2 H, m), 4.28 - 4.10 (2 H, m), 4.05 - 3.90 (1 H, m), 3.95 - 3.60 (7 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H, m), 2.80 - 2.65 (2 H, m), 2.00 - 1.80 (1 H, m) MW (calcd):382.4; MW : 383.2 (M+1) Step 2: 2-((S)-I -[I,4]dtoxanylmetnoxy)(4-nydroxy-butyl)-6, 7—dt'nydro-pyrt'mt'do[6, I -a]t'soqut'nolt'none (Compound 15]).
Compound 151 was prepared Via general method I using intermediate 32.
Compound 152: 9-(cyclohexyl-methyl—amino)((S)[1,4]dioxanylmethoxy)-6,7-dihydropyrimido [6,1 -a]isoquinolinone. o ON K/o K/O o’é /E N ’ N ’ | | 0*“ 01“ Q Q N N H | nd 147 nd 152 Mel (0.007 mg, 0.11 mmol, 1.2 eq.) was added to compound 147 (38 mg, 0.092 mmol, 1 eq.) and NaH (6 mg, 0.15 mmol, 1.6 eq.) in DMF (5 mL) and the reaction was stirred at RT for 16 h. Some more NaH (6 mg, 0.15 mmol, 1.6 eq.) and Mel (0.07 mg, 0.11 mmol, 1.2 eq.) were added to the reaction mixture and it was stirred for a fithher 2 days. The mixture was quenched with brine and ted with EtOAc. The organic layers were dried over MgSO4 and evaporated to dryness. The residue was d by preparative HPLC-MS to provide compound 152.
(H, CDC13) 5 ppm 7.57 - 7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H, s), 4.51 - 4.33 (2 H, m), 4.26 — 3.93 (1 H, m), 3.92 - 4.14 (2 H, m), 4.06 - 3.56 (6 H, m), 3.56 - 3.41 (1 H, m), 3.00 - 2.90 (2 H, m), 2.88 (3 H, s), 2.04 — 1.63 (2 H, m), 1.60 - 1.31 (5 H, m), 1.28 - 1.08 (1 H, m) MW (calcd): 425.5; MW (obsd): 426.4 Compound 153: 9-(cyclohexylmethyl-amino)—2-((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 - a]isoquinolinone.
This compound is ed via general method J using intermediate 13 and cyclohexanecarbaldehyde.
Compound 154: 2-((S)[1,4]dioxanylmethoxy)[(tetrahydro-pyranylmethyl)-amino]-6,7-dihydropyrimido [6,1 -a]isoquinolinone.
This compound is prepared via general method J using intermediate 13 and tetrahydro-pyran carbaldehyde.
Compound 155: 2-((S)-1 -[1,4]dioxanylmethoxy)—9-(3-ethylhydroxy-pentyl)-6,7 -dihydro-pyrimido[6,1 - a]isoquinolinone. ofi ofi ofi O/2 O/ 0/2 Step 1 Step 2 N’ —.— N/ _ . N, o’/J\N I | | o N o N OTf Q Intermediate 9 Intermediate 33 nd 155 Step I .' 2-((S)-I -[I ,4]Dt0xanylmeth0xy)(3-ethyl—3-hydr0xy-pent—I -ynyl)-6, 7—dthydr0-pyrtmtd0[6,1- ajtsoqutnoltn0ne (Intermediate 33) Intermediate 33 is prepared Via general method G using intermediate 9 and 3-ethy1-pentynol. (1H, CDC13) 5 ppm 7.51 - 7.46 (1 H, m), 7.28 - 7.24 (1 H, m), 7.22 - 7.19 (1 H, m), 6.20 (1 H, s), 4.30 - 4.19 (2 H, m), 4.08 - 4.00 (2 H, m), 3.87 - 3.79 (1 H, m), 3.75 - 3.47 (5 H, m), 3.39 - 3.30 (1 H, m), 3.03 (1 H, br.
S), 2.88 - 2.80 (2 H, m), 1.746 - 1.56 (4 H, m), 0.97 (6 H, s) MW (calcd): 424.5; MW (obsd): 425.5 (M+1) Step 2: 2-((S)-I -[1,4]dioxan-Z-ylmethoxy)-9— (3ethylhydr0xy-pentyl)-6, dro-pyrt'mt'do[6, I - ajtsoqutnoltn0ne (Compound 155).
Compound 155 is prepared Via general method I using ediate 33.
Compound 156: 2-((S)[1 ,4]dioxany1methoxy)(3 -hydroxy—3 -methy1-buty1)-6,7-dihydro- pyrimido [6,1 quinolinone o/\ o/\ 0 $0 o _ K/o O/2 O/2 0/2 Step 1 Step 2 i’ —> —> I i’ I i’ I O N O N O N OTf Q Intermediate 9 Intermediate 34 Compound 156 Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)-9 -(3-hydr0xymethyl—but—I -ynyl)-6, 7—dt'hydr0-pyrt'mt'd0[6,1 - ajtsoqutnolin0ne (Intermediate 34) Intermediate 34 is prepared Via general method G using intermediate 9 and 2-methyl-butyn (H, CDC13) 5 ppm 7.58 (1 H, d), 7.38 - 7.33 (1 H, m), 7.32 - 7.29 (1 H, m), 6.32 (1 H, s), 4.43 - 4.32 (2 H, m), 4.18 - 4.12 (2 H, m), 3.99 - 3.91 (1 H, m), 3.87 - 3.58 (5 H, m), 3.50 - 3.42 (1 H, m), 2.97 - 2.90 (2 H, m), 1.60 (6 H, s) MW ): 396.4; MW (obsd): 397.3 (M+1) Step 2: 2-((S)-I -[I ,4]dioxanylmethoxy)-9—(3-hydroxymethyl—butyZ)-6, 7—dt'nydro-pyrt'mt'do[6,1 - a]isoquinolinone (Compound 156)
[00428] Compound 156 is ed Via general method I using ediate 34.
Compound 157 : 2-((S)-1 dioxanylmethoxy)(3 -hydroxy-pentyl)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
O O O K/0 K/0 $0 0,: 0,: 0,: Step 1 Step 2 j: —’ i —’ I | i | O N O N O N OTf % Intermediate 9 Intermediate 35 Compound 157 Step I .' 2-((S)-I -[I ,4]Dioxanylmethoxy)(3-hydroxy-pent—I -ynyl)-6, 7—dt'nydro-pyrt'mt'do[6,1 - a]isoquinolinone (Intermediate 35) Intermediate 35 is prepared Via general method G using intermediate 9 and pentynol. (1H, CDC13) 8 ppm 7.62 - 7.57 (1 H, m), 7.41 - 7.35 (1 H, m), 7.33 (1 H, s), 6.34 (1 H, s), 4.60 - 4.53 (1 H, m), 4.45 - 4.33 (2 H, m), 4.20 - 4.14 (2 H, m), 4.00 - 3.92 (1 H, m), 3.88 - 3.59 (5 H, m), 3.51 - 3.42 (1 H, m), 2.99 - 2.90 (2 H, m), 1.90 - 1.74 (2 H, m), 1.07 (3 H, t) Step 2: 2-((S)-I -[I ,4]dtoxanylmethoxy)-9—(3-nydroxy-pentyZ)-6, 7—dt'nydro-pyrt'mt'do[6,1 -a]t'soquinolt'n one und 15 7)
[00430] Compound 157 is prepared Via general method I using intermediate 35.
Compound 1 58: 9-(2 ,2 -dimethyl-propoxy)((S)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone.
Synthesis fiJlly described above. 1 l3 WO 92791 Compound 159: 2-((S)— 1 -[1 ,4]di0xanylmeth0xy)(tetrahydr0-pyranylmeth0xy)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method L with intermediate 6 and methanesulfonic acid tetrahydro-pyranylmethyl ester.
Compound 160: 2-((S)-1 -[1,4]di0xanylmeth0xy)(4-hydr0xymethyl-pentyl)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne. o/\ o 0 K/0 K/0 K/0 0,: ,2 ,2 Step 1 Step 2 N ’ " N ’ ’ N ’ OékN I OékN I OékN I OTf Q OH Intermediate 9 Intermediate 36 Compound 160 Step I .' 2-((S)-I -[I,4]Dt0xanylmeth0xy)(4—hydr0xymethyZ-pent-I -ynyZ)-6, 7-dihydr0-pyrimtd0[6,1 - ajtsoqutnolin0ne (intermediate 36) A Vial was charged with intermediate 9 (0.15 g, 0.324 mol, 1 eq.), 2-methyltrimethylsilanyl- pentynol (66 mg, 0.389 mmol, 1.2 eq), CuI (2.5 mg, 0.013 mmol, 0.04 eq.), iPrZNH (0.41 mL, 2.92 mol, 9 eq.) and THF (2 mL). The solution was purged with Ar for 15 min., and Pd(PPh3)C12 (11 mg, 0.016 mmol, 0.05 eq.) was added with TBAF (0.39 mL, 0.39 mmol, 1.2 eq., 1M in THF). The Vial was sealed and the reaction was heated to 80 °C for 16 h. The reaction mixture was evaporated to dryness and the crude product was purified by preparative TLC eOH, 98/2] to afford intermediate 36 2-((S)[1,4]di0xan- 2-ylmeth0xy)(4-hydr0xymethyl-pentynyl)-6,7-dihydr0-pyrimid0 [6, 1 -a]is0quinolin0ne. (1H, CDC13) 5 ppm 7.70 - 7.58 (1 H, m), 7.45 - 7.38 (1 H, m), 7.35 (1 H, s), 6.37 (1H, s), 4.50 - 4.30 (2 H, m), 4.28 - 4.15 (2 H, m), 4.05 - 3.95 (1 H, m), 3.95 - 3.55 (5 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.95 (2 H, m), 2.62 (2 H, s), 1.39 (6 H, s) MW (calcd): 410.5; MW (obsd): 411.4 Step 2: 2-((S)-I -[I,4]dt0xanylmeth0xy)(4-hydr0xy-4—methyl—pentyl)-6, dr0-pyrimtd0[6,1 - ajtsoqutnolin0ne (Compound 160) nd 160 is prepared Via general method I using intermediate 36.
Compound 161: [1,4]dioxanylmeth0xy)—9-(tetrahydr0-pyranylmeth0xymethyl)-6,7-dihydr0- pyrimido [6,1 -a]is0quinolin0ne. l 14 This compound is prepared via general method E using ediate 9 and potassium 4- (tetrahydropyranylmethoxy)methyltrifluoroborate.
Compound 162: 2-([1 ,4]dioxanylmethoxy)methoxy-6,7 -dihydro-pyrimido[[6, 1 -a]isoquinolinone H NJOLN/fio/ St—>ep1NfLNM©\ H M Intermediate 1 Intermediate 37 0/fi [Step 2 Step 3 N / CAN I Compound 162 Intermediate 38 Step I .' I -[2-(3-meth0xy—phenyl)-ethyl]-pyrimidine-2,4,6—tri0ne (intermediate 3 7) Sodium (236 mg, 10.2 mmol, 2 eq.) was added to degassed EtOH (18 mL), when sodium dissolved completely, ethyl te (1.56 mL, 10.2 mmol, 2 eq.) was added and the reaction was d for 1 h. Intermediate 1 (995 mg, 5.12 mol, 1 eq.) in EtOH (4 mL) was then added and the reaction was refluxed for 1 day. The desired intermediate 37 1-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione precipitated upon on of 2N s HCl, it was filtered and washed with H20 and finally dried. (1H, DMSO-d6) 5 ppm 7.27 - 7.18 (1 H, m), 6.84 - 6.72 (3 H, m), 3.92 - 3.83 (2 H, m), 3.75 (3 H, s), 3.62 (2 H, s), 2.80 - 2.70 (2 H, m) MW (calcd): 262.3; MW (obsd): 263.3 (M+1) Step 2: 2-chlor0meth0xy-6, 7-dihydr0-pyrimid0[6,1 -a]isoquinolin0ne (intermediate 38) Intermediate 37 (920 mg, 3.51 mol, 1 eq.) was heated in POC13 (5 mL) at 50°C for 2 days. The les were evaporated under vacuum, the residue was dissolved in DCM and washed with a saturated aqueous solution ofNaHC03, before drying over MgSO4. Evaporation of the organic phase gave intermediate 38 2-chloromethoxy—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, which was used in the next step without further purification. (1H, CDC13) 6 ppm 7.73 - 7.66 (1 H, m), 6.98 - 6.90 (1 H, m), 6.85 - 6.80 (1 H, m), 6.69 (1 H, s), 4.00 - 4.20 (2 H, m), 3.91 (3 H, s), 3.04 (2 H, m) Step 3: 2-([I ,4]di0xanylmelh0xy)melh0xy-6, 7—dihydr0-pyrimid0[6,1-a]is0quinolin0ne (compound I 62) ioxanyl-methanol (42 mg, 0.36 mol, 2 eq.) was dissolved in DCM (3 mL) with NaH (14 mg, 0.36 mmol, 2 eq., 60% in mineral oil). After 30 min, intermediate 38 (50 mg, 0.18 mmol, 1 eq.) was added to the mixture and the reaction was stirred at RT for 16h. The reaction mixture was evaporated to dryness and the crude product was purified by preparative HPLC-MS to provide compound 162.
(H, CDC13) 8 ppm 7.68 - 7.62 (1 H, m), 6.95 - 6.87 (1 H, m), 6.82 - 6.77 (1 H, m), 6.29 (1 H, s), 4.51 - 4.35 (2 H, m), 4.26 — 3.92 (1 H, m), 3.91 — 2.94 (2 - 4.17 (2 H, m), 4.05 - 3.60 (8 H, m), 3.55 - 3.44 (1 H, m), 3.04 H, m) MW (calcd): 344.4; MW (obsd): 345.0 Compound 163: [1,4]dioxanylmethoxy)(oxetanylmethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone.
This compound is prepared via general method L using intermediate 6 and methanesulfonic acid oxetan-3 -ylmethyl ester.
Compound 164: yclopropyl-propoxy)((R)[1,4]dioxanylmethoxy)—6,7-dihydropyrimido[6,1 - a]isoquinolinone.
A solution of intermediate 6 (1.15 g, 3.48 mol, 1 eq.) and opropanol (0.349 g, 3.48 mmol, 1eq.) in 1,4-dioxane was degassed with Argon for 10 min. PPh3 (1.096 g, 4.18 mmol, 1.2 eq.) was added and the reaction mixture was degassed with Argon an onal 5 min. DIAD (0.745 mL, 3.83 mmol, 1.1 eq.) was added dropwise at 0°C. The reaction e was stirred at RT for 16 h. opropylpropan 01 (0.150 mg, 1.49 mmol, 0.43 eq.) and PPh3 (0.30 g, 1.14 mmol, 0.33 eq.) were added. The reaction mixture was cooled to 0°C and DIAD (0.350 mL, 1.80 mmol, 5.2 eq.) was added. After 1 h at RT, the reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography on silica-gel to afford compound 164. (1H, DMSO-dg) 5 ppm 7.93 (1H, d), 6.97-6.92 (2 H, m), 6.53 (1H, s), 4.24-4.23 (2H, m), 4.08 (2H, t), 4.00 (2H, t), 3.98-3.74 (3H, m), 3.68-3.57 (2H, m), 3.51-3.48 (1H, m), 3.37 (1H, t), 2.96 (2H, t), 1.84-1.80 (2H, m), 1.36-1.30 (2H, m), 0.81-0.63 (1H, m), 0.42-0.39 (2H, m), 0.04-0.02 (2H, m) MW (calcd): 412.5; MW (obsd): 413.0 (M+1) C0mpound 1 65: [1 ,4 ]dioxanylmethoxy)-9 -(3 -methoxy-propyl) -6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone.
K/o K/o K/o 0/- 0/: /: Step 1 Step 2 31/ —) —> I 31/ I 31/ I O N O N O N OTf Q 0\ Intermediate 9 Intermediate 39 Compound 165 Step I .' 2-((S)-I -[I,4]Dt'oxanylmethoxy)(3-methoxy-prop-I -ynyl)-6, 7—dt'hydro-pyrtmtdo[6, I - ajt'soqut'nolt'none (Intermediate 39) ] Intermediate 39 was ed Via general method G using intermediate 9 and 3-methoxy—propyne. (1H, CDC13) 5 ppm 7.68 (1 H, d), 7.48 (1 H, d), 7.42 (1 H, s), 6.40 (1 H, s), 4.50 - 4.41 (2 H, m), 4.38 (2 H, s), 4.23 (2 H, t), 4.05 - 3.98 (1 H, m), 3.89 - 3.70 (5 H, m), 3.55 - 3.50 (4 H, m), 3.03 (2 H, t) MW (calcd): 382.4; MW (obsd): 383.4 (M+1) Step 2: 2-((S)-I-[I,4]dtoxanylmethoxy)(3-methoxy-propyl)-6,7—dt'hydro-pyrt'mtdo[6,I-ajt'soqut'nolt'n one (Compound 165) Compound 165 was prepared Via general method I using intermediate 39. 1 5 C0mpound 1 66: 2-((S)-1 - [1 ,4 ]dioxanylmethoxy)-9 - [2 -(1 -hydroxy-cyclopentyl)-ethyl] -6,7-dihydro- pyrimido [6,1 -a]isoquinolinone. 0/} o 0 $0 $0 K/o O; 0,: ,2 Step 1 Step 2 N’ —’ N/ —’ N/ OAN I DAN I DAN I % OH Intermediate 9 Intermediate 40 nd 166 Step I .' 2-((S)-I -[I ,4]Dt'oxanylmethoxy)(I -hydroxy-cyclopentylethynyl)-6, 7—dt'hydro-pyrt'mt'do[6,1 - ajt'soqut'nolt'none (Intermediate 40)
[00443] ediate 40 is prepared Via general method G using intermediate 9 and 3-methoxy—propyne. (1H,CDC13)6 ppm 7.54 (1 H, d), 7.31 (1 H, d), 7.26 (1 H, s), 6.28 (1 H, s), 4.39 - 4.30 (2 H, m), 4.12 (2 H, t), 3.95 — 3.91 (1 H, m), 3.82 — 3.58 (5 H, m), 3.50 (1 H, m), 3.16 (1 H, s), 2.89 (2 H, t), 2.05 - 1.98 (4 H, m), 1.90 — 1.70 (4H, m) Step 2: 2-((S)-I -[I , 4]dioxanylmethoxy)[2-(1 -nydroxy-cyclopentyl)-ethyl]-6, 7—dtnydro-pyrt'mtdo[6,1 - uinolinone (Compound 166) Compound 166 was prepared Via l method I using intermediate 40.
Compound 167 : 2-((R)[1 ,4]Dioxanylmethoxy)-9 -(4-hydroxy-tetrahydro-pyranylethynyl)-6,7 - dihydro-pyrimido[6,1 -a]isoquinolinone.
This compound is prepared Via general method G using intermediate 10 and 4-Ethynyl—tetrahydro- pyranol.
Compound 168: 2-((R)-1 - [1 ,4]Dioxanylmethoxy)-9 -(3 -methoxy-propyl)-6 ,7 -dihydro-pyrimido [6 ,1 - a]isoquinolinone #0 #0 3" O O 0 Step 1 Step 2 N ’ —> N ’ —> N ’ OAN I OAN I OAN I OTf % 0\ ediate 10 Intermediate 41 Compound 168 Step I .' 2-((R)-I -[I,4]Dtoxanylmethoxy)—9—(3-methoxy-prop-I -ynyZ)-6, 7—dihydro-pyrtmtdo[6, I - a]isoquinoltnone (Intermediate 40) Intermediate 41 is prepared Via l method G using intermediate 10 and 3-methoxy-propyne. (1H, CDC13) ppm 7.56 (l H, d), 7.48 (l H, d), 7.33 (l H, s), 6.27 (l H, s), 4.32 - 4.27 (2 H, m), 4.23 (2 H, s), 4.08 (2 H, t), 3.88 - 3.85 (l H, m), 3.76 - 3.49 (5 H, m), 3.40 - 3.34 (4 H, m), 2.90 (2 H, t) Step 2: 2-((R)-I-[I,4]dtoxanylmethoxy)(3-methoxy-propyZ)-6,7—dihydro-pyrtmtdo[6,I-ajt'soqut'nolt'n one (Compound 165)
[00447] Compound 168 is prepared Via general method I using intermediate 41.
Compound 169: 2-((R)[1,4]Dioxanylmethoxy)[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydropyrimido [6,1 -a]isoquinolinone ofi 0% 0% 50 50 50 O O 0 Step 1 Step 2 N / —- N / —» N / A ' A ' A ' O N O N O N Intermediate 10 Intermediate 42 Compound 169 Step I .' 2-((S)-I -[I,4]Di0xanylmelh0xy)(I -hydr0xy-cyclopenZJ/ZelhynyD-d 7—dihydr0-pyrl'ml'd0[6,1 - a]isoquinolin0ne mediate 42) ] ediate 42 is prepared Via general method G using intermediate 10 and 1-Ethyny1— cyclopentanol. (1H, CDC13) 8 ppm 7.47 (1 H, d), 7.25 (1 H, d), 7.20 (1 H, s), 6.22 (1 H, s), 4.32 - 4.24 (2 H, m), 4.05 (2 H, t), 3.88 — 1.90 (4H, m), 1.85 - 3.85 (1H, m), 3.77 - 3.52 (5 H, m), 3.38 (1H, t), 2.83 (2 H, t), 2.02 - 1.67 (4H, Step 2: 2-((R)-I -[I,4]Di0xanylmelh0xy)(I -hydr0xy-cyclopenZJ/ZelhynyD-d dr0-pyrl'ml'd0[6,1 - a]isoquinolin0ne (Compound 169) Compound 169 is prepared Via general method I using intermediate 42.
Compound 170: 2-((S)[1,4]Dioxany1methoxy)(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1- a]isoquinolinone O O N / N ’ 0%N I I —> 0%N /\/O\/\ OH O Intermediate 6 Compound 170 Intermediate 6 (0.15 g, 0.45 mol, 1 eq.), 2-Propoxy—ethanol (63 ”L, 0.55 mmol, 1.2 eq.) and PPh3 (144 mg, 0.55 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was degassed with N2. DIAD (0.108 mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT overnight. 0.5 eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature for an extra 2h.
Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgSO4 and concentrated. Crude product was purified on silicagel column to give compound 170.
Compound 171: 2-((S)-1 -[1,4]Dioxanylmethoxy)—9-(2-isopropoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone Q Q o/ 0 ediate 6 Compound 171 Intermediate 6 (0.15 g, 0.45 mol, 1 eq.), 2-isopropoxy-ethanol (63 uL, 0.55 mmol, 1.2 eq.) and PPh3 (144 mg, 0.55 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was ed with N2. DIAD (0.108 mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT for 5 h. 0.5 eq. of DIAD and PPh3 were added, and the on mixture was stirred at room temperature overnight. Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified on silicagel column to give compound 171.
Compound 172: 2-((R)[1 ,4]Dioxanylmethoxy)-9 -(2-propoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 - a]isoquinolinone 0 5/0 0 O O N ’ 0%N /\/O\/\ OH O ediate 7 Compound 172 Intermediate 7 (0.25 g, 0.76 mol, 1 eq.), 2-Propoxy-ethanol (105 ”L, 0.91 mmol, 1.2 eq.) and PPh3 (238 mg, 0.91 mmol, 1.2 eq.) were suspended in 1,4-dioxane (10 mL) and the mixture was degassed with N2. DIAD (0.180 mL, 0.91 mmol, 1.2 eq.) was added and the reaction was stirred at RT overnight. 0.3 eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature for an extra 24h.
Reaction mixture was d with brine, extracted with EtOAc, dried over MgSO4 and concentrated. Crude t was purified on silicagel column to give compound 172. nd 173: 2-((R)-1 -[1,4]Dioxanylmeth0xy)—9-(2-is0pr0p0xy-eth0xy)-6,7 -dihydr0-pyrimid0 [6,1 - a]is0quin01in0ne o/\ o/\ 5O 5O O O N / N/ OAN | | —> 02‘ OH ONOY Intermediate 7 Compound 173 ] Intermediate 7 (0.25 g, 0.76 mol, 1 eq.), r0p0xy—ethanol (105 ”L, 0.91 mmol, 1.2 eq.) and PPh3 (238 mg, 0.91 mmol, 1.2 eq.) were suspended in 1,4-di0xane (10 mL) and the mixture was ed with N2. DIAD (0.180 mL, 0.91 mmol, 1.2 eq.) was added and the on was stirred at RT for 5 h. 0.3 eq. 0f DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature overnight. Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgSO4 and trated. Crude product was purified on silicagel column to give compound 173.
Compound 174: 2-((S)[1,4]Dioxanylmeth0xy)—9-(4-meth0xy-butyl)-6,7-dihydr0-pyrimid0[6,1- a]is0quin01in0ne Step I .' potassium 3-melhoxy-propyl—Zrfluoroborare /O\/\/Br /O\/\/BF3K Intermediate 43 In a 2-neck round bottom flask equipped with a reflux condenser and an addition funnel was charged with Mg (471 mg, 19.20 mol, 3 eq.) and EtzO (2 mL) under N2. One drop of neat (2-br0m0-ethyl)- cyclopropane was added followed by two drops of dibromoethane. Once the 1St bubbles appeared, 1-Br0m0- 3-methoxy-propane (1 g, 6.54 mol, 1 eq.) in EtZO (10 mL) was added dropwise. Upon completion of the addition, the resulting suspension was stirred at RT for 1 h. In a separate flask, purged with N2, a solution made of B(OMe)3 (1.1 mL, 9.81 mmol, 1.5 eq.) in THF (12 mL) was cooled to -78 °C. To this solution, the 3- methoxy-propyl magnesium bromide suspension was added dropwise via a double ended needle. The mixture was d to stir for 1 h at -78 °C and then was warmed to RT for 1 h. After cooling the mixture to 0 °C, a saturated aqueous on of KHFZ (5.8 mL, 4.5 M, 4.1 eq.) was added dropwise and the reaction e was allowed to warm to RT. After 30 min, the solution was concentrated in-vacuo. The dried solids were triturated with hot acetone and filtered to remove inorganic salts. The resulting filtrate was concentrated and the solid residue was ated with Et20. Potassium 3-methoxy-propyl-trifluoroborate, intermediate 43, was filtered and dried in-vacuo. (1H, DMSO-d6) 5 ppm 3.19 — 3.13 (5 H, m), 1.38 — 1.29 (2 H, m), -0.1 - 0.19 (2 H, m) Step 2: 2-((S)-I-[I,4]Dioxanylmeth0xy)(4—melh0xy-bulyl)-6,7-dihydr0-pyrimid0[6,I-ajisoquinolin Compound 174 is prepared Via general method E using intermediates 9 and 43.
[00456] Table 11: Mass spectral data of the Compounds of the Invention MW: Molecular weight calc: ated obs: ed Structures Name MW MW (calc) 0(bsd) 9 -Allyloxy—2-([1,4]dioxan ylmethoxy)-6,7 -dihydro- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxanylmethoxy)-9 - pyridin-3 -yl-6,7 -dihydropyrimido [6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxanylmethoxy)-9 - pyridinyl-6,7 -dihydropyrimido [6, 1 -a] isoquinolin WO 92791 2-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile 3-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile [1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile [2-([1,4]Dioxany1meth0xy)- 4-0x0-6,7-dihydr0-4H- pyrimid0[6,1-a]isoquinolin yloxy]—acet0nitrile 2-([1 ,4]Dioxany1meth0xy)-9 - (0xaz01—2-y1meth0xy)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne Structures Name (calc) 2-([1 ,4]Dioxany1meth0xy)-9 - (pyridin-Z-ylmethoxy)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 9 -(3 ,5 0r0-pheny1) ([1,4]dioxany1meth0xy)-6 ,7 - o-pyrimid0[6, 1 - a] isoquinolin0ne l(0) 9 -B enzofuran-2 -y1 ([1,4]dioxany1meth0xy)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 12 4H-pyrimid0[6,1-a]isoquinolin- 9-y1]-ind01e-1 -carb0xylic acid tert-butyl ester 2012/076275 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (1H-ind01—2-y1)-6 ,7 -dihydr0- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (6-meth0xy-pyridin-3 -y1)—6,7 - dihydro-pyrimid0[6, 1 - a] nolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (6-triflu0r0methy1—pyridin-3 - y1)-6,7-dihydr0-pyrimid0[6,1- a] isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -methy1—3 H-imidaz01 1 6 ylethynyl)-6,7-dihydr0- pyrimido[6, 1 -a] isoquinolin 9 -(5 -tert-Buty1— o [1,2,4]0xadiaz01—3 -y1meth0xy)- 17 2-([1,4]dioxany1meth0xy)— 6,7-dihydr0-pyrimido[6,1- a] isoquinolin0ne -[2-([1,4]Di0xan oxy)—4-0x0-6,7-dihydr0- 18 4H-pyrimid0 [6,1 -a]isoquin01in- 9-y1] -pyridinecarb0xy1ic acid methylamide 2-( [1 ,4 ]Di0xany1meth0xy)-9 - pentyny1-6 ,7 -dihydr0- pyrimido[6, 1 -a] is0quin01in 2-( [1 ,4 ]Di0xany1meth0xy)-9 - (2-pyridiny1—ethy1)—6,7- dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-([1 ,4]Di0xany1meth0xy)-9 - (2-pyrazin-2 -y1- ethy1)-6,7- dihydro-pyrimid0[6, 1 - a]isoquin01in0ne 2-( [1 ,4 ]Di0xany1meth0xy)-9 - (1H-ind01—5 -y1)-6 ,7 -dihydr0- do[6, 1 -a] is0quin01in 2-([1 ,4]Dioxany1meth0xy)-9 - h0xy-pheny1)—6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (5 -meth0xy-pyridin-3 -y1)—6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-([1 ,4]Dioxany1meth0xy)-9 - (1H-indaz01—5 -y1)-6,7-dihydr0- pyrimid0[6,1-a]isoquinolin 2-([1 ,4]Dioxany1meth0xy)-9 - (4-meth0xy-pheny1)—6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 3-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzamide -[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]flu0r0-benzamide N—{3-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- imid0 [6,1 -a]isoquinoliny1] -pheny1} -acetamide 9 -Cyclopr0py1ethynyl ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-([1 ,4]Dioxany1meth0xy)-9 - (1 -hydr0xy- 3 1 cyclopentylethyny1)-6,7- o-pyrimid0[6, 1 - a]isoquinolin0ne WO 92791 2-([1,4]Dioxany1methoxy) pyrimidin-5 --y16,7-d1hydro- pyrimido[6, 1 a—]150qu1nolin ohex-eny12- ([1 4,]dioxany1methoxy)-6,7- d1hydro-pyr1m1do[6, 1- a]1soqu1nolinone 2-([1 ,4]Dioxany1methoxy) (1-methy1—1H-1ndoly1)-6,7- d1hydro-pyr1m1do[6, 1- a]1soqu1nolinone 2-([1 ,4]Dioxany1methoxy) (6-methyl—pyridin-3 --y1)6,7- d1hydro-pyr1m1do[6, 1- a]1soqu1nolinone 2-( [1 ,4 ]Dioxany1meth0xy)-9 - pyridin-Z-ylethyny1-6,7- dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -meth0xy-pr0p-1 -yny1)—6,7- dihydro-pyrimid0[6, 1 - a] isoquinolin0ne -[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]-pentynenitrile 2-([1 xany1meth0xy)-9 - (3 -hydr0xy—pr0pyny1)—6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (4-meth0xy—phenylethynyl)-6 ,7 - o-pyrimid0[6, 1 - a] isoquinolin0ne WO 92791 Structures Name MW (calc) (0 2-( [1 ,4 ]Dioxany1meth0xy)-9 - n-3 -ylethyny1-6 ,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 4-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]-N-methy1—benzamide 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -meth0xy-pheny1)—6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 9-(2-Ch10r0-pheny1) ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne Structures Name MW (calc) 2-( [1 ,4 ny1methoxy)-9 - (4-hydroxy-but-1 -6 ,7 - dihydro-pyrimido[6, 1 - a] isoquinolinone 9 -(1 ,5 -Dimethy1— 1 H-pyraz01-3 - ylmethoxy)([1,4]dioxan 46 yhnethoxy)-6,7 -dihydro- pyrimido[6, 1 -a] isoquinolin I 2-( [1 ,4 ]Dioxany1methoxy)-9 - (1 -methy1—1H-pyrazol—3 - 47 yhnethoxy)-6,7 -dihydro- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -methy1—[1,2,4]oxadiazol—5 - 48 yhnethoxy)-6,7 -dihydro- pyrimido[6, 1 -a] isoquinolin Structures Name MW (calc) (0 2-([1 ,4]Dioxany1meth0xy)-9 - (4-m0rpholiny1-pheny1)-6,7- o-pyrimid0[6, 1 - a]isoquinolin0ne 3-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]flu0r0-benzamide 3-[2-([1,4]Dioxan oxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0[6,1-a]isoquinolin- 9-y1]—5-flu0r0-benzamide 9-(3 ,3 -Dimethy1—butyny1) ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - pyridinylethyny1-6 ,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -methy1—isoxaz01—5 - 54 ylmethoxy)-6,7 r0- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -hydr0xy-3 -methy1—but 55 ynyl)—6,7-dihydr0- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (2-meth0xy-pyridin-3 -y1)—6,7 - dihydro-pyrimid0[6, 1 - a] nolin0ne 2-([1 ,4]Dioxany1meth0xy)— 57 6,7-dihydr0-pyrimid0[6,1- a]isoquinolin0ne Structures Name (calc) 9-(3,6-Dihydr0-2H-pyrany1)- 2-([1 ,4]dioxany1meth0xy)- 6,7-dihydr0-pyrimido[6,1- a]isoquinolin0ne -[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]-pyridinecarb onitrile 2-([1 ,4]Dioxany1meth0xy)-9 - (6-isoprop0xy-pyridin-3 -y1)- hydr0-pyrimido[6,1- a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - 0xy—pyridin-3 -y1)-6 ,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne Structures Name (calc) I O 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (6-m0rpholiny1-pyridin-3 - y1)-6,7-dihydr0-pyrimid0[6,1- a] isoquinolin0ne 9 -(2,3 -Dimeth0xy-phenyl) ([1,4]dioxany1meth0xy)-6 ,7 - ;I(NW) dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 9 -(3 0meth0xy- pyridiny1)( [1 ,4]dioxan ylmethoxy)-6,7 r0- 456 pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (2-methy1—pyridiny1)-6 ,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne Structures Name (calc) 3-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]—isonicotin0nitrile 9 -(2,5 -Dimeth0xy-phenyl) ([1,4]dioxany1meth0xy)-6 ,7 - dihydro-pyrimid0[6, 1 - a] nolin0ne 2-([1 ,4]Dioxany1meth0xy)-9 - (3,4,5,6-tetrahydr0-2H- [1 ,2']bipyridiny1—5 '-y1)-6,7- 475 dihydro-pyrimid0[6, 1 - uinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (2-eth0xy—pyridin-3 -y1)-6 ,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne Structures Name (calc) 9 Dimeth0xy—pyridin-3 - y1)([1 ,4]dioxan 70 ylmethoxy)-6,7 -dihydr0- pyrimido[6, 1 -a] isoquinolin 4-[2-([1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinolin- 9-y1]-nicotin0nitrile 9-tert-But0xymethy1—2- ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ny1meth0xy)-9 - (2-pyrrolidin-1 -y1-pyridin-3 -y1)- 6,7-dihydr0-pyrimido[6,1- a] isoquinolin0ne 2-( [1 ,4 ]Di0xany1meth0xy)-9 - (6-pyrr01idin-1 -y1-pyridin-3 -y1)- 6,7-dihydr0-pyrimido[6,1- a] is0quin01in0ne 2-( [1 ,4 ny1meth0xy)-9 - (5 -pheny1—oxaz01-2 - ylmethoxy)-6,7 r0- pyrimido[6, 1 -a] is0quin01in 9 -(5 -tert-Buty1—0xaz01—2- ylmethoxy)([1,4]di0xan ylmethoxy)-6,7 -dihydr0- pyrimido[6, 1 -a] is0quin01in 9 -(5 -Cyclopr0py1— [1 ,2,4] oxadiaz01-3 -y1meth0xy)- 2-([1 xany1meth0xy)- 6,7-dihydr0-pyrimido[6,1- a]is0quin01in0ne 2-( [1 ,4 ]Di0xany1meth0xy)-9 - (5 -ethy1— [1 ,2 ,4] oxadiaz01-3 - ylmethoxy)-6,7 -dihydr0- pyrimido[6, 1 -a] is0quin01in 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (5 -methy1—[1,2,4]0xadiaz01—3 - ylmethoxy)-6,7 -dihydr0- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ny1meth0xy)-9 - (5 -isopr0py1—[ 1 ,2,4]0xadiaz01— 3 -y1meth0xy)—6,7-dihydr0- pyrimido[6, 1 -a] nolin 9 -Cyclopentylethyny1-2 - ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 9-Cyclohexy1ethyny1—2- ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne WO 92791 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -methy1—butyny1)-6,7 - dihydro-pyrimido[6, 1 - a] isoquinolinone 2-( [1 ,4 ]Dioxany1methoxy)-9 - hexyny1—6 ,7 -dihydropyrimido [6, 1 -a] isoquinolin 9 - [3 -(B enzyl-methyl—amino)- propyny1]-2 -( [1 ,4]dioxan yhnethoxy)-6,7 -dihydropyrimido [6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -hydroxy-5 -methy1—hex yny1)-6,7-dihydropyrimido [6, 1 -a] nolin 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -hydroxy-but-1 -yny1)-6 ,7 - dihydro-pyrimido[6, 1 - a] isoquinolinone ng Structures Name MW MW (calc) (obsd) 9-Cyclopropy1—2-([1 ,4]dioxan- 2-y1methoxy)—6,7-dihydro- pyrimido[6,1-a]isoquinolin 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -hydroxy-pentyny1)-6,7 - dihydro-pyrimido[6, 1 - a] isoquinolinone 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -hydroxymethy1—pent yny1)-6,7-dihydropyrimido [6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 -ethy1—3 -hydroxy-pent 9 yny1)-6,7-dihydro- do[6, 1 -a] isoquinolin one I 2-( [1 ,4 ]Dioxany1methoxy)-9 - (3 xy-3 -pheny1-but-1 - 92 yny1)-6,7-dihydropyrimido [6, 1 -a] isoquinolin 9 -(3 -Benzylamino-prop-1 - yny1)([1,4]dioxan 93 ylmethoxy)-6,7 ropyrimido [6, 1 -a] isoquinolin Structures Name (calc) (obsd) 2-( [1 ,4 ]Dioxany1meth0xy)-9 - [(furan-Z-y1methy1)-amin0]—6,7- dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-([1 ,4]Dioxany1meth0xy)-9 - (1 -ethy1—1H-pyraz01y1)-6,7- o-pyrimid0[6, 1 - a]isoquinolin0ne 2-([1 ,4]Dioxany1meth0xy)-9 - [1 -(3 -methy1—buty1)-1 H- pyraz01y1]-6,7-dihydr0- 451 pyrimid0[6,1-a]isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (5 -methy1—furany1)-6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne ures Name (calc) 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -hydr0xy-hexyny1)-6 ,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 9 -(3 ,5 -Dimethy1—1H-pyraz01—4- y1)([1 ,4]dioxan ylmethoxy)-6,7 -dihydr0- pyrimido[6, 1 -a] isoquinolin 2-([1 xany1meth0xy)-9 - (1 H-pyraz01y1)-6,7-dihydr0- pyrimid0[6,1-a]isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (1 -pr0py1—1H-pyraz01—4-y1)-6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne Structures Name (calc) (R)—1-[1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- 4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile 2-[2-((S)—1-[1,4]Dioxan ylmethoxy)—4-0x0-6,7-dihydr0- imid0 [6,1 -a]isoquinolin- 9-y1]—benz0nitrile 9 -(5 -Cyclopr0py1— [1 ,2,4] oxadiaz01-3 -y1meth0xy)- 2-((R)[1,4]dioxan ylmethoxy)-6,7 -dihydr0- pyrimido[6, 1 -a] isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - ethyny1-6 ,7 -dihydr0- pyrimido[6, 1 -a] isoquinolin 2-([1 ,4]Dioxany1meth0xy)-9 - pyrimidin-Z-ylethynyl-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -pheny1amin0-pr0pyny1)- hydr0-pyrimido[6,1- a] isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -hydr0xy—3 -pyridin-3 -y1- prop-1 -6,7-dihydr0- pyrimido[6, 1 -a] isoquinolin 9-Cyclopenty10xymethy1—2- ([1,4]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -meth0xymethy1—pent yny1)-6,7-dihydr0- pyrimido[6, 1 -a] isoquinolin ng Structures Name MW MW (calc) (obsd) 9-Cyclopr0py1ethyny1—2-((R)-1 - [1 ,4]dioxany1meth0xy)-6,7- dihydro-pyrimid0[6, 1 - 37 379 a]isoquinolin0ne II 2-((S)—1-[1,4]Dioxan ylmethoxy)—9-(3 -methy1-but-1 - ynyl)—6,7-dihydr0- 380 38 1 pyrimid0[6,1-a]isoquinolin 2-( [1 ,4 ]Dioxany1meth0xy)-9 - (3 -imidaz01— 1 -y1-pr0p-1 -yny1) - 4 1 8 1 9 6,7-dihydr0-pyrimido[6,1- a] nolin0ne 9-(2-Cyclopropyl—ethyl)—2-((R)[1,4]dioxany1meth0xy)- 382 383 6,7-dihydr0-pyrimido[6,1- a]isoquinolin0ne 9-Cyclopenty10xymethy1—2- ((R)—1-[1,4]dioxan ylmethoxy)-6,7 -dihydr0- pyrimid0[6,1-a]isoquinolin 2-( [1 ,4 ny1meth0xy)-9 - (3 -hydr0xy—3 -pyridin-3 -y1- propy1)-6 ,7 -dihydr0 - pyrimido[6, 1 -a] isoquinolin 9 -A11y10xy—2-((R) [1 xany1meth0xy)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 9 -A11y10xy—2-((S)-1 - [1 ,4 ]dioxany1meth0xy)-6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-((R)[1,4]Dioxan ylmethoxy)(tetrahydr0- pyrany10xymethy1)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-( [1 ,4 ]Dioxany1meth0xy)-9 - {3 - [(pyridin-3 -y1methy1)— amino] 1 -yny1} -6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-((R)[1,4]Dioxan ylmethoxy)-9 -penty1-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 9-Cyclopropylethynyl-Z-((S)-1 - [1 ,4]dioxany1meth0xy)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 9-(2-Cyclopropyl—ethyl)—2-((S)[1,4]dioxany1meth0xy)- 6,7-dihydr0-pyrimido[6,1- a]isoquinolin0ne : 2-((S)—1-[1,4]Dioxan O/ oxy)-9 -(0xetan-3 - 124 yloxymethyl)—6,7-dihydr0- 400 401 | pyrimido[6, 1 -a] isoquinolin O N one 2-((S)—1-[1,4]Dioxan yhnethoxy)-9 -(3 -methyl- oxetan-3 -y1methoxymethy1)- 6,7-dihydro-pyrimido[6,1- a] isoquinolinone -Dimethy1—buty1amino)-2 - ((S)[1,4]dioxan yhnethoxy)-6,7 -dihydropyrimido [6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan yhnethoxy)(3 -hydroxy-4 - methyl-penty1)-6 ,7 -dihydro- pyrimido[6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan oxy)—9-(2-ethy1— hexylamino)-6,7-dihydro- pyrimido[6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan oxy)(2-methoxy— ethoxy)-6 ,7 -dihydropyrimido [6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)-9 -(2-eth0xy— ethoxy)-6 ,7 -dihydr0- do[6, 1 -a] nolin 9-Cyclopr0py1meth0xy—2-((S)[1,4]dioxany1meth0xy)- 6,7-dihydr0-pyrimido[6,1- a]isoquinolin0ne 2-((S)—1-[1,4]Dioxan ylmethoxy)—9-(2-flu0r0- ethoxy)-6 ,7 -dihydr0- pyrimid0[6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)-9 - [3 -(2-meth0xy— ethoxy)-pr0pyny1]—6,7 - dihydro-pyrimid0[6, 1 - a] isoquinolin0ne 2-((S)—1-[1,4]Dioxan ylmethoxy)—9 - [3 -(2-eth0xy- ethoxy)-pr0pyny1]—6,7 - dihydro-pyrimid0[6, 1 - a] nolin0ne 2-((S)—1-[1,4]Dioxan ylmethoxy)—9-[3-(2-flu0r0- ethoxy)-pr0pyny1]—6,7- dihydro-pyrimid0[6,1- a]isoquinolin0ne 9 -(2,2-Dimethy1— propoxymethy1)((S) [1 ,4]dioxany1meth0xy)-6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 9-Cyclohexyloxymethyl-Z-((S)[1,4]dioxany1meth0xy)- 6,7-dihydr0-pyrimido[6,1- uinolin0ne 9-Cyclopropylmethoxymethyl- 2-((S)[1,4]dioxan ylmethoxy)-6,7 -dihydr0- pyrimid0[6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)(tetrahydr0- pyran-Z-ylmethoxy)—6,7- dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-((S)—1-[1,4]Dioxan ylmethoxy)(3 xy— buty1)-6,7-dihydr0- pyrimid0[6,1-a]isoquinolin 9 -(4 ,4 -Dimethy1—pentyloxy) ((S)[1,4]dioxan yhnethoxy)-6,7 -dihydropyrimido [6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan yhnethoxy)-9 -(3 -methoxy—4- methyl-penty1)-6 ,7 ropyrimido [6, 1 -a] isoquinolin 9 -(3 propy1—propoxy) ((S)[1,4]dioxan yhnethoxy)-6,7 -dihydro- pyrimido[6, 1 -a] isoquinolin 9 -Cyclohexy1amino((S)— 1 - [1 ,4]dioxany1methoxy)-6,7- dihydro-pyrimido[6, 1 - a]isoquinolinone 2-((S)—1-[1,4]Dioxan ylmethoxy)(3 -hydroxy—4,4- dimethyl—penty1)-6,7-dihydropyrimido [6,1-a]isoquinolin opentylmethoxymethyl- 2-((S)[1,4]dioxan yhnethoxy)-6,7 -dihydropyrimido [6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)—9-(3 -methoxy— -6,7-dihydro- pyrimido[6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)—9-(3 -pheny1aminopropy1 )-6 ,7 -dihydro - pyrimido[6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)(4-hydroxy— penty1)-6 ,7 -dihydro- pyrimido[6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)(4-hydroxy— buty1)-6,7-dihydropyrimido [6,1-a]isoquinolin 2012/076275 9-(Cyclohexyl-methyl-amino)- 2-((S)[1,4]dioxan yhnethoxy)-6,7 -dihydro- pyrimido[6,1-a]isoquinolin 9-(Cyclohexylmethyl-amino)-2 - ((S)[1,4]dioxan yhnethoxy)-6,7 -dihydropyrimido [6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)[(tetrahydropyrany1methyl )-amino]-6,7- dihydro-pyrimido[6, 1 - a]isoquinolinone 2-((S)—1-[1,4]Dioxan yhnethoxy)-9 -(3 -ethy1—3 - hydroxy-penty1)-6 ,7 ro- pyrimido[6, 1 -a] isoquinolin ng Structures Name MW MW (calc) (obsd) 2-((S)—1-[1,4]Dioxan yhnethoxy)(3 -hydroxy-3 - methyl-buty1)-6,7-dihydro- 400 40 1 pyrimido[6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)(3 -hydroxy— penty1)-6 ,7 -dihydro- 400 40 1 pyrimido[6, 1 -a] isoquinolin 9 -(2,2-Dimethy1—propoxy) ((S)[1,4]dioxan yhnethoxy)-6,7 -dihydro- 400 40 1 pyrimido[6, 1 -a] isoquinolin —1-[1,4]Dioxan oxy)(tetrahydropyrany1methoxy )—6,7- 28 29 dihydro-pyrimido[6, 1 - a]isoquinolinone 2-((S)—1-[1,4]Dioxan yhnethoxy)(4-hydroxy methyl-penty1)-6 ,7 -dihydropyrimido ]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)(tetrahydropyrany1methoxymethyl )-6,7- dihydro-pyrimido[6, 1 - a]isoquinolinone 2-([1 ,4]Dioxany1methoxy)-9 - methoxy—6,7-dihydro- pyrimido[6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan yhnethoxy)-9 -(oxetan-3 - yhnethoxy)-6,7 ro- pyrimido[6, 1 -a] isoquinolin 9 -(3 -Cyclopropy1—propoxy) ((R)—1-[1,4]dioxan yhnethoxy)-6,7 -dihydropyrimido [6,1-a]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)—9-(3 -meth0xy— propy1)-6 ,7 -dihydr0 - pyrimido[6, 1 -a] isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)-9 -[2-(1 -hydr0xy— cyclopenty1)-ethy1] -6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-((R)[1,4]Dioxan ylmethoxy)(4-hydr0xy— tetrahydro-pyranylethyny1)- hydr0-pyrimido[6,1- a]isoquinolin0ne 2-((R)[1,4]Dioxan ylmethoxy)—9-(3 -meth0xy— propy1)-6 ,7 -dihydr0 - do[6, 1 -a] isoquinolin 2-((R)[1,4]Dioxan ylmethoxy)-9 -[2-(1 -hydr0xy— cyclopenty1)-ethy1] -6,7 - dihydro-pyrimid0[6, 1 - a]isoquinolin0ne 2-((S)—1-[1,4]Dioxan ylmethoxy)(2-propoxyethoxy )-6 ,7 -dihydro- pyrimido[6,1-a]isoquinolin —1-[1,4]Dioxan yhnethoxy)(2-isopropoxy— ethoxy)-6,7 -dihydropyrimido [6,1-a]isoquinolin 2-((R)[1,4]Dioxan ylmethoxy)(2-propoxy- ethoxy)-6 ,7 -dihydropyrimido [6,1-a]isoquinolin 2-((R)[1,4]Dioxan yhnethoxy)(2-isopropoxy— ethoxy)-6 ,7 -dihydropyrimido ]isoquinolin 2-((S)—1-[1,4]Dioxan ylmethoxy)(4-methoxy— buty1)-6,7-dihydropyrimido [6,1-a]isoquinolin WO 92791 Table III: NMR Data of the Compounds of the Invention de# NMR data (8) (1H, CDC13) 6 ppm 7.61 (1 H, d), 6.89 (1 H, dd), 6.78 (1 H, d), 6.26 (1 H, s), 6.13 — 5.94 (1 H, m), 5.48 - 5.24 (2 H, m), 4.59 (2 H, dt), 4.48 - 4.30 (2 H, m), 4.18 (2 H, t), 4.10 - 4.02 (1 H, m), 3.96 (1 H, m), 3.89 — 3.57 (4 H, m), 3.46 (1 H, dd), 2.95 (2 H, t) (1H, CDC13) 8 ppm 8.89 (1 H, s), 8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1 H, d), 7.61 (1 H, d), 7.53 (1 H, s), 7.43 (1 H, dd), 6.43 (1 H, s), 4.51 - 4.37 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, m), 3.92 — 3.60 (5 H, m), 3.49 (1 H, m), 3.10 (2 H, t) (1H, CDC13) 8 ppm 8.77 (2 H, br. s.), 7.86 (1 H, d), 7.76 — 7.46 (4 H, m), 6.48 (1 H, br. s.), 4.60 — 4.36 (2 H, m), 4.30 (2 H, br. s.), 4.04 (1 H, br. s.), 3.94 — 3.67 (5 H, m), 3.54 (1 H, t), 3.15 (2 H, br. s.) (1H, CDC13) 8 ppm 7.83 — 7.53 (4 H, — 7.94 (2 H, m), 7.78 — 7.71 (1 H, m), 7.67 4 m), 6.48 (1 H, s), 4.53 — 4.43 (2 H, m), 4.34 - 4.27 (2 H, m), 4.07 - 4.01 (1 H, m), 3.93 — 3.67 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t) (1H, CDC13) 8 ppm 7.90 (1 H, d), 7.87- 7.79(2 H, m), 7.73 — 7.69 (1 H, m), 7.65 — 7.56 (2 H, m), 7.52 (1 H, s), 6.45 (1 H, s), 4.51 - 4.37 (2 H, m), 4.27 (2 H, t), 4.06 — 3.95 (1 H, m), 3.91 — 3.61 (5 H, m), 3.51 (1 H, dd), 3.11 (2 H, t) (1H, CDC13) 8 ppm 7.85 — 7.68 (5 H, m), 7.61 (1 H, dd), 7.54 (1 H, d), 6.44 (1 H, 6 s), 4.51 - 4.36 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m), 3.91 — 3.61 (5 H, m), 3.50 (1 H, dd), 3.11 (2 H, t) (1H, CDC13) 8 ppm 7.71 (1 H, d), 7.00 (1 H, dd), 6.90 (1 H, d), 6.31 (1 H, s), 4.86 7 (2 H, s), 4.51 - 4.34 (2 H, m), 4.22 (2 H, t), 3.99 (1 H, m), 3.92 — 3.58 (5 H, m), 3.49 (1 H, dd), 3.03 (2 H, t) (1H, CDC13) 8 ppm 7.72 (1 H, d), 7.68 — 7.60 (1 H, m), 7.18 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.23 (2 H, s), 4.49 - 4.33 (2 H, m), 4.19 (2 H, t), 4.02 — 3.94 (1 H, m), 3.89 — 3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t) (H CDC13) 8 ppm 8.63 (1 H, d), 7.75 (1 H, td), 7.64 (1 H, d), 7.50 (1 H, d), 7.29 — 7.24 (1 H, m), 6.99 (1 H, dd), 6.89 (1 H, d), 6.27 (1 H, s), 5.29 (2 H, d), 4.48 — 4.34 (2 H, m), 4.19 (2 H, t), 4.02 — 3.93 (1 H, m), 3.90 — 3.60 (5 H, m), 3.48 (1 H, dd), 2.97 (2 H, t) (1H, CDC13) 8 ppm 7.79 (1 H, d), 7.56 (1 H, d), 7.49 (3 H, d), 7.40 (1 H, s), 6.42 (1 H, s), 4.51 - 4.36 (2 H, m), 4.25 (2 H, t), 4.00 (1 H, m), 3.91 — 3.60 (5 H, m), 3.50 (1 H, t), 3.09 (2 H, t) WO 92791 de# NMR data (8) (1H, CDC13) 8 ppm 7.87 (1 H, d), 7.83 — 7.76 (2 H, m), 7.64 (1 H, d), 7.56 (1 H, d), 7.41 — 7.32 (1 H, m), 7.31 — 7.23 (3 H, m), 7.18 (1 H, s), 6.43 (1 H, s), 4.46 (2 H, ,_1 ,_1 br. s.), 4.27 (2 H, t), 4.06 — 3.96 (1 H, m), 3.97 — 3.61 (5 H, m), 3.51 (1 H, t), 3.11 (2 H, t) (1H, CDC13) 8 ppm 8.20 (1 H, d), 7.76 (1 H, d), 7.60 (1 H, d), 7.47 (1 H, dd), 7.42 — 7.35 (2 H, m), 7.336 — 7.26 (1 H, m), 6.68 (1 H, s), 6.44 (1 H, s), 4.54 - 4.40 (2 ,_1 [\J H, m), 4.27 (2 H, t), 4.08 — 3.96 (1 H, m), 3.91 — 3.65 (5 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.42 (9 H, s) (H DMSO-d6) 8 ppm 8.11 (1 H, d), 7.95 — 7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H, d), 7.15 (1 H, t), 7.10 (1 H, d), 6.71 (1 H, s), 4.31 - 4.25 (2 H, m), 4.09 (2 H, t), ,_1 DJ 3.92 — 3.84 (1 H, m), 3.79 (2 H, td), 3.71 — 3.57 (2 H, m), 3.55 — 3.46 (1 H, m), 3.40 (1 H, dd), 3.08 (2 H, t) (1H, CDC13) 8 ppm 8.45 (1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.56 (1 H, dd), 7.50 ,_1 4; — 7.46 (1 H, m), 6.87 (1 H, d), 6.43 (1 H, s), 4.49 — 4.36 (2 H, m), 4.30 - 4.19 (2 H, m), 4.04 — 3.98 (4 H, m), 3.93 — 3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t) (1H, CDC13) 8 ppm 8.97 (1 H, d), 8.09 (1 H, dd), 7.83 (2 H, dd), 7.63 (1 H, dd), 7.55 (1 H, s), 6.44 (1 H, s), 4.52 — 4.36 (2 H, m), 4.27 (2 H, t), 3.99 (1 H, tt), 3.91 - 3.59 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t) (1H, CDC13) 8 ppm 7.73 (1 H, d), 7.57 — 7.50 (2 H, m), 7.48 — 7.45 (1 H, m), 7.42 ,_1 (1 H, d), 6.42 (1 H, s), 4.53 - 4.39 (2 H, m), 4.28 — 4.23 (2 H, m), 4.07 — 3.97 (1 H, m), 3.94 — 3.64 (8 H, m), 3.52 (1 H, dd), 3.06 (2 H, t) (1H, CDC13) 8 ppm 7.66 (1 H, d), 7.03 (1 H, dd), 6.94 (1 H, d), 6.29 (1 H, s), 5.22 (2 H, s), 4.50 - 4.33 (2 H, m), 4.27 — 4.14 (2 H, m), 4.03 — 3.93 (1 H, m), 3.90 — 3.61 (5 H, m), 3.49 (1 H, dd), 2.99 (2 H, t), 1.47 (9 H, s) (1H, CDC13) 8 ppm 8.80 (1 H, d), 8.32 (1 H, d), 8.16 — 7.96 (2 H, m), 7.85 (1 H, d), ,_1 7.65 (1 H, dd), 7.57 (1 H, s), 6.45 (1 H, s), 4.56 — 4.37 (2 H, m), 4.28 (2 H, t), 4.01 (1 H, qd), 3.93 — 3.60 (5 H, m), 3.58 — 3.44 (1 H, m), 3.20 — 3.02 (5 H, m) (1H, CDC13) 8 ppm 7.65 (1 H, d), 7.41 (1 H, dd), 7.36 (1 H, s), 6.38 (1 H, s), 4.50 — ,_1 4.40 (2 H, m), 4.28 _ 4.18 (2 H, m), 4.01 (1 H, m), 3.92 — 3.66 (5 H, m), 3.52 (1 H, dd), 3.01 (2 H, t), 2.45 (2 H, t), 1.68 (2 H, sxt), 1.09 (3 H, t) (1H, CDC13) 8 ppm 8.58 (1 H, dd), 7.66 — 7.56 (2 H, m), 7.22 (1 H, dd), 7.19 — 7.09 [\JO (3 H, m), 6.36 (1 H, s), 4.50 — 4.36 (2 H, m), 4.25 — 4.17 (2 H, m), 4.04 - 3.95 (1 H, m), 3.91 — 3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4 H, s), 2.98 (2 H, t) WO 92791 de# NMR data (8) (1H, CDC13) 8 ppm 8.55 (1 H, dd), 8.44 (2 H, dd), 7.63 (1 H, d), 7.22 (1 H, dd), [\J ,_1 7.15 (1 H, s), 6.36 (1 H, s), 4.53 — 3.95 — 4.36 (2 H, m), 4.26 — 4.17 (2 H, m), 4.07 (1 H, m), 3.93 — 3.61 (5 H, m), 3.51 (1 H, dd), 3.17 (4 H, s), 2.99 (2 H, t) (1H, CDC13) 8 ppm 8.51 (1 H, br. s.), 7.94 (1 H, s), 7.79 — 7.67 (2 H, m), 7.61 (1 H, s), 7.58 — 7.47 (2 H, m), 7.33 (1 H, t), 6.67 (1 H, br. s.), 6.43 (1 H, s), 4.56 — 4.40 (2 H, m), 4.29 (2 H, t), 4.04 (1 H, td), 3.97 — 3.65 (5 H, m), 3.61 — 3.48 (1 H, m), 3.11 (2 H, t) (1H, CDC13) 8 ppm 7.76 (1 H, d), 7.58 (1 H, d), 7.50 (1 H, s), 7.45 — 7.32 (2 H, m), DJ 7.13 — 7.01 (2 H, m), 6.43 (1 H, s), 4.45 (2 H, m), 4.27 (2 H, t), 4.01 (1 H, m), 3.94 — 3.63 (8 H, m), 3.52 (1 H, t), 3.08 (2 H, t) (1H, CDC13) 6 ppm 8.56 - 8.45 (1 H, m), 8.38 (1 H, d), 7.83 (1 H, d), 7.63 (1 H, N4; dd), 7.54 (1 H, s), 7.42 (1 H, t), 6.45 (1 H, s), 4.54 - 4.36 (2 H, m), 4.31 - 4.23 (2 H, m), 4.05 — 3.96 (4 H, m), 3.93 — 3.62 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t) (1H, CDC13) 8 ppm 8.17 (1 H, d), 8.01 (1 H, s), 7.78 (1 H, d), 7.72 — 7.60 (3 H, m), [\J LII 7.57 (1 H, d), 6.42 (1 H, s), 4.52 - 4.38 (2 H, m), 4.32 - 4.24 (2 H, m), 4.01 (1 H, qd), 3.93 — 3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t) (1H, CDC13) 8 ppm 7.74 (1 H, d), 7.57 (3 H, d), 7.48 (1 H, s), 7.01 (2 H, d), 6.40 (1 H, s), 4.51 - 4.36 (2 H, m), 4.25 (2 H, t), 3.99 (1 H, dd), 3.92 — 3.60 (8 H, m), 3.50 (1 H, t), 3.06 (2 H, t) (1H, CDC13) 8 ppm 8.18 (1 H, s), 7.84 (3 H, d), 7.68 (1 H, dd), 7.64 — 7.55 (2 H, [\J \1 m), 6.47 (1 H, s), 4.57 — 3.98 (1 H, m), 3.96 — 4.39 (2 H, m), 4.30 (2 H, t), 4.09 — 3.64 (5 H, m), 3.54 (1 H, dd), 3.13 (2 H, t) (1H, CDC13) 8 ppm 8.45 (1 H, dd), 7.88 — 7.74 (2 H, m), 7.65 (1 H, d), 7.58 (1 H, 00 s), 7.36 — 7.25 (1 H, m), 6.46 (1 H, s), 4.57 — 4.40 (2 H, m), 4.29 (2 H, t), 4.03 (1 H, td), 3.96 — 3.64 (5 H, m), 3.60 — 3.46 (1 H, m), 3.12 (2 H, t) (H, CDC13) 8ppm 7.99 (1 H, s), 7.80 (1 H, d), 7.64 (1 H, d), 7.56 (1 H, s), 7.50 — 7.32 (3 H, m), 6.45 (1 H, s), 4.56 — 3.97 (1 H, - 4.40 (2 H, m), 4.29 (2 H, t), 4.11 m), 3.95 — 3.64 (5 H, m), 3.60 — 3.46 (1 H, m), 3.11 (2 H, t), 2.26 (5 H, s) (1H, CDC13) 8 ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.33 (1 H, s), 6.41 — 6.34 (1 H, 0 m), 4.53 - 4.39 (2 H, m), 4.29 — 4.18 (1 H, m), 4.06 — 3.97 (1 H, m), 3.93 — 3.64 (5 H, m), 3.52 (1 H, dd), 3.00 (2 H, t), 1.56 — 0.83 (4 H, m) — 1.45 (1 H, m), 1.01 (1H, CDC13) 8 ppm 7.67 (1 H, d), 7.45 (1 H, dd), 7.39 (1 H, s), 6.40 (1 H, s), 4.53 — DJ ,_1 4.38 (2 H, m), 4.31 - 4.17(2 H, m), 4.02 (1 H, dd), 3.94 — 3.64 (5 H, m), 3.52 (1 H, dd), 3.08 — 2.96 (2 H, m), 2.18 — 1.75 (7 H, m), 1.29 (1 H, 5) de# NMR data (8) (1H, CDC13) 6 ppm 9.32 (1 H, s), 9.04 (2 H, s), 7.90 (1 H, d), 7.66 (1 H, dd), 7.58 [\J (1 H, s), 6.48 (1 H, s), 4.56 — 3.99 (1 H, - 4.40 (2 H, m), 4.37 - 4.27 (2 H, m), 4.11 m), 3.96 — 3.64 (5 H, m), 3.60 — 3.46 (1 H, m), 3.17 (2 H, t) (H, CDC13) 8 ppm 7.67 (1 H, d), 7.42 (1 H, d), 7.32 (1 H, s), 6.39 (1 H, s), 6.31 (1 H, t), 4.54 - 4.38 (2 H, m), 4.25 (2 H, t), 4.02 (1 H, dd), 3.94 — 3.64 (5 H, m), 3.53 (1 H, t), 3.03 (2 H, t), 2.45 (2 H, d), 2.29 (2 H, dd), 1.91 - 1.58 (4 H, m) (1H, 6) 8 ppm 8.07 (1 H, d), 7.97 (1 H, s), 7.78 — 7.72 (2 H, m), 7.62 — 7.53 (2 H, m), 7.39 (1 H, d), 6.68 (1 H, s), 6.52 (1 H, d), 4.33 — 4.24 (2 H, m), 4.09 (2 H, t), 3.91 — 3.76 (5 H, m), 3.71 — 3.58 (2 H, m), 3.55 — 3.47 (1 H, m), 3.40 (1 H, m), 3.29 (1 H, s), 3.10 (2 H, t) (1H, CDC13) 6 ppm 8.84 (1 H, d), 7.96 (1 H, d), 7.85 (1 H, d), 7.64 (1 H, dd), 7.56 DJ LII (1 H, s), 7.40 (1 H, d), 6.47 (1 H, s), 4.55 - 4.40 (2 H, m), 4.37 - 4.23 (2 H, m), 4.04 (1 H, m), 3.95 — 3.65 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t), 2.74 (3 H, 5) (1H, CDC13) 8 ppm 8.69 (1 H, d), 7.78 — 7.72 (2 H, m), 7.65 — 7.57 (3 H, m), 7.33 DJ 0\ (1 H, m), 6.43 (1 H, s), 4.54 - 4.39 (2 H, m), 4.27 (2 H, t), 4.05 (1 H, s), 3.95 — 3.64 (5 H, m), 3.53 (1 H, dd), 3.07 (2 H, t) (1H, CDC13) 8 ppm 7.68 (1 H, d), 7.47 (1 H, dd), 7.42 (1 H, s), 6.40 (1 H, s), 4.53 — 4.41 (2 H, m), 4.38 (2 H, s), 4.24 (2 H, t), 4.07 — 3.96 (1 H, m), 3.93 — 3.63 (5 H, m), 3.55 — 3.33 (4 H, m), 3.03 (2 H, t) (1H, CDC13) 8 ppm 7.67 (1 H, d), 7.44 (1 H, dd), 7.39 (1 H, s), 6.39 (1 H, s), 4.50 — DJ 00 4.40 (2 H, m), 4.26 - 4.20 (2 H, m), 4.04 — 3.98 (1 H, m), 3.91 — 3.65 (5 H, m), 3.52 (1 H, dd), 3.02 (2 H, t), 2.90 — 2.83 (2 H, m), 2.75 - 2.68 (2 H, m) (H CDC13) 8 ppm 7.64 (1 H, d), 7.42 (1 H, dd), 7.37 (1 H, s), 6.38 (1 H, s), 4.51 (2 H, s), 4.48 - 4.378 (2 H, m), 4.19 (2 H, t), 4.03 — 3.96 (1 H, m), 3.89 — 3.64 (5 H, m), 3.51 (1 H, dd), 2.99 (2 H, t) (1H, CDC13) 8 ppm 7.65 (1 H, d), 7.50 — 7.44 (3 H, m), 7.41 (1 H, s), 6.94 — 6.84 (2 H, m), 6.35 (1 H, s), 4.45 - 4.36 (2 H, m), 4.19 (2 H, t), 4.04 — 3.91 (1 H, m), 3.87 — 4;0 3.62 (8 H, m), 3.48 (1 H, dd),7.81 (1 H, d), 7.59 — 7.48 (2 H, m), 7.43 (1 H, s), 7.41 — 7.33 (3 H, m), 6.47 (1 H, s), 4.54 - 4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 — 3.65 (5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t) (1H, CDC13) 8 ppm 8.78 (1 H, d), 8.59 (1 H, dd), 7.83 (1 H, dt), 7.71 (1 H, d), 7.54 (1 H, dd), 7.49 (1 H, s), 7.39 — 7.25 (1 H, m), 6.40 (1 H, s), 4.51 - 4.33 (2 H, m), 4.30 — 3.93 (1 H, m), 3.90 — 4.16 (2 H, m), 4.07 — 3.59 (5 H, m), 3.49 (1 H, dd), 3MQH0 WO 92791 de# NMR data (8) (1H, CDC13) 5 ppm 7.93 (2 H, d), 7.78 (1 H, d), 7.72 — 7.59 (3 H, m), 7.54 (1 H, s), 4;N 6.42 (1 H, s), 4.49 - 4.35(2 H, m), 4.23 (2 H, t), 4.05 — 3.95 (1 H, m), 3.91 — 3.61 (5 H, m), 3.49 (1 H, t), 3.16 — 2.97 (5 H, m) (H, CDC13) 6 ppm 7.81 (1 H, d), 7.64 (1 H, d), 7.55 (1 H, br. s.), 7.50 - 7.37 (1 H, m), 7.24 (1 H, d), 7.18 (1 H, br. s.), 7.00 (1 H, d), 6.46 (1 H, br. s.), 4.47 (2 H, d), 4.30 (2 H, br. s.), 4.04 (1 H, br. s.), 3.98 - 3.66 (7 H, m), 3.54 (1 H, t), 3.12 (2 H, br. s.), 1.83 (1 H, br. s.) (1H, CDC13) 5 ppm 7.81 (1 H, d), 7.59 — 7.48 (2 H, m), 7.43 (1 H, s), 7.41 — 7.33 (3 H, m), 6.47 (1 H, s), 4.54 - 4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 — 3.65 (5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t) (1H, CDC13) 5 ppm 7.62 (1 H, d), 7.39 (1 H, d), 7.34 (1 H, s), 6.36 (1 H, s), 4.51 — 4; U) 4.34 (2 H, m), 4.19 (2 H, t), 3.99 (1 H, td), 3.91 — 3.59 (7 H, m), 3.50 (1 H, dd), 2.98 (2 H, t), 2.74 (2 H, t) (H CDC13) 5 ppm 7.64 (1 H, d), 7.02 (1 H, dd), 6.92 (1 H, d), 6.30 (1 H, s), 6.13 4; 0\ (1 H, s), 5.09 (2 H, s), 4.51 — 4.36 (2 H, m), 4.22 (2 H, t), 4.07 - 3.97 (1 H, m), 3.92 — 3.61 (8 H, m), 3.57 — 3.44 (1 H, m), 2.99 (2 H, t), 2.30 (3 H, s) (1H, CDC13) 5ppm 7.62 (1 H, d), 7.37 (1 H, d), 7.00 (1 H, dd), 6.90 (1 H, d), 6.33 (1 H, d), 6.27 (1 H, s), 5.12 (2 H, s), 4.47 - 4.34 (2 H, m), 4.23 - 4.143 (2 H, m), 4.02 — 3.89 (4 H, m), 3.88 — 3.59 (5 H, m), 3.48 (1 H, dd), 2.96 (2 H, t) (1H, CDC13) 5 ppm 7.67 (1 H, d), 6.99 (1 H, dd), 6.90 (1 H, d), 6.29 (1 H, s), 5.33 4; 00 (2 H, s), 4.47 - 4.35 (2 H, m), 4.20 (2 H, t), 4.03 — 3.93 (1 H, m), 3.89 — 3.60 (5 H, m), 3.48 (1 H, dd), 2.99 (2 H, t), 2.45 (3 H, s) (H CDC13) 5 ppm 7.77 (1 H, d), 7.66 — 7.57 (3 H, m), 7.52 (1 H, d), 7.04 (2 H, d), 6 6.43 (1 H, s), 4.55 - 4.40 (2 H, m), 4.35 — 4.24 (2 H, m), 4.04 (1 H, dd), 3.97 — 3.66 (9 H, m), 3.54 (1 H, dd), 3.32 — 3.20 (4 H, m), 3.10 (2 H, s) (1H, CDC13) 5 ppm 8.06 (1 H, dd), 7.92 — 7.78 (2 H, m), 7.63 (1 H, d), 7.56 (1 H, s), 7.36 — 7.24 (1 H, m), 6.47 (1 H, s), 4.55 - 4.38 (2 H, m), 4.28 (2 H, t), 4.13 - 3.99 (1 H, m), 3.95 — 3.65 (5 H, m), 3.54 (1 H, t), 3.11 (2 H, t) (1H, CDC13) 5 ppm 7.95 (1 H, t), 7.80 (1 H, d), 7.67 — 7.54 (3 H, m), 7.54 — 7.45 (1 ,_1 H, m), 6.44 (1 H, s), 4.52 - 4.35 (2 H, m), 4.31 - 4.19 (2 H, m), 4.09 — 3.96 (1 H, m), 3.95 — 3.64 (5 H, m), 3.58 — 3.46 (1 H, m), 3.10 (2 H, t) (1H, CDC13) 5 ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, d), 6.38 (1 H, s), 4.52 — LI] [\J 4.39 (2 H, m), 4.26 - 4.16 (2 H, m), 4.04 — 3.96 (1 H, m), 3.93 — 3.63 (5 H, m), 3.51 (1 H, dd), 3.00 (2 H, t), 1.36 (9 H, 5) WO 92791 de# NMR data (8) (1H, CDC13) 5 ppm 8.72 — 8.64 (2 H, m), 7.75 (1 H, d), 7.59 (1 H, dd), 7.54 (1 H, s), 7.48 — 7.42 (2 H, m), 6.44 (1 H, s), 4.55 - 4.39 (2 H, m), 4.34 - 4.22 (2 H, m), 4.03 (1 H, dd), 3.95 — 3.64 (5 H, m), 3.53 (1 H, dd), 3.08 (2 H, t) (1H, CDC13) 5 ppm 7.68 (1 H, d), 6.98 (1 H, dd), 6.89 (1 H, d), 6.31 (1 H, s), 6.23 (1 H, s), 5.22 (2 H, s), 4.52 - 4.36 (2 H, m), 4.29 - 4.18 (2 H, m), 4.07 — 3.96 (1 H, m), 3.93 — 3.63 (5 H, m), 3.51 (1 H, dd), 3.06 — 2.96 (2 H, m), 2.35 (3 H, s) (1H, CDC13) 5 ppm 7.60 (1 H, d), 7.39 — 7.35 (1 H, m), 7.32 (1 H, d), 6.33 (1 H, s), LII LII 4.45 - 4.35 (2 H, m), 4.17 (2 H, t), 3.97 (1 H, m), 3.87 — 3.60 (5 H, m), 3.47 (1 H, dd), 2.95 (2 H, t), 1.62 (6 H, s) (1H, CDC13) 5 ppm 8.24 (1 H, dd), 7.78 (1 H, d), 7.67 (1 H, dd), 7.61 (1 H, dd), LII 0\ 7.54 (1 H, s), 7.04 (1 H, dd), 6.45 (1 H, s), 4.52 - 4.41 (2 H, m), 4.28 (2 H, t), 4.02 (4 H, s), 3.93 — 3.64 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t) (1H, CDC13) 5 ppm 7.70 (1 H, d), 7.43 (1 H, dd), 7.33 (1 H, d), 6.39 (1 H, s), 6.31 LII 00 (1 H, dt), 4.53 - 4.34 (4 H, m), 4.31 - 4.19 (2 H, m), 4.06 — 3.94 (3 H, m), 3.92 — 3.61 (5 H, m), 3.51 (1 H, dd), 3.04 (2 H, t), 2.62 - 2.50 (2 H, m) (H, CDC13) 5 ppm 9.02 (1 H, d), 8.09 (1 H, dd), 7.97 — 7.80 (2 H, m), 7.67 (1 H, dd), 7.59 (1 H, d), 6.48 (1 H, s), 4.56 — 4.38 (2 H, m), 4.36 - 4.25 (2 H, m), 4.03 (1 H, m), 3.95 — 3.63 (5 H, m), 3.53 (1 H, dd), 3.16 (2 H, t) (1H, CDC13) 5 ppm 8.43 (1 H, d), 7.86 — 7.74 (2 H, m), 7.56 (1 H, dd), 7.47 (1 H, d), 6.80 (1 H, d), 6.43 (1 H, s), 5.44 — 5.31 (1 H, m), 4.53 - 4.37 (2 H, m), 4.26 (2 H, t), 4.01 (1 H, m), 3.92 - 3.62 (5 H, m), 3.51 (1 H, dd), 3.09 (2 H, t), 1.40 (6 H, (1H, CDC13) 5 ppm 8.44 (1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.57 (1 H, dd), 7.48 ,_1 (1 H, d), 6.85 (1 H, d), 6.43 (1 H, s), 4.54 - 4.37 (4 H, m), 4.27 (2 H, t), 4.02 (1 H, m), 3.93 — 3.62 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t), 1.45 (3 H, t) (1H, CDC13) 5 ppm 8.52 (1 H, d), 7.85 — 7.72 (2 H, m), 7.56 (1 H, dd), 7.47 (1 H, d), 6.75 (1 H, d), 6.42 (1 H, s), 4.52 — 4.38 (2 H, m), 4.32 - 4.22 (2 H, m), 4.06 - 3.97 (1 H, m), 3.93 — 3.58 (13 H, m), 3.52 (1 H, dd), 3.09 (2 H, s) (1H, CDC13) 5 ppm 7.77 (1 H, d), 7.60 (1 H, dd), 7.52 (1 H, d), 7.21 - 7.12 (1 H, O\ m), 6.99 (2 H, ddd), 6.45 (1 H, s), 4.53 — 4.40 (2 H, m), 4.28 (2 H, t), 4.06 — 3.98 (1 H, m), 3.95 (3 H, s), 3.92 — 3.63 (8 H, m), 3.52 (1 H, dd), 3.08 (2 H, t) (H, CDC13) 5 ppm 8.15 (1 H, d), 7.82 (1 H, d), 7.50 (1 H, dd), 7.45 — 7.40 (1 H, O\4; m), 6.91 (1 H, d), 6.46 (1 H, s), 4.54 - 4.40 (2 H, m), 4.29 (2 H, t), 4.11 (2 H, s), 4.07 — 3.98 (1 H, m), 3.94 — 3.64 (4 H, m), 3.53 (1 H, dd), 3.11 (2 H, t) WO 92791 de# NMR data (8) (1H, CDC13) 8 ppm 8.62 (1 H, d), 7.84 (1 H, d), 7.67 (1 H, dd), 7.59 (1 H, d), 7.42 (1 H, s), 7.36 (1 H, dd), 6.46 (1 H, s), 4.54 - 4.38 (2 H, m), 4.33 - 4.24 (2 H, m), 4.07 — 3.97 (1 H, m), 3.94 — 3.63 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t), 2.68 (3 H, (H, CDC13) 8 ppm 8.88 (1 H, s), 8.82 (1 H, d), 7.88 (1 H, d), 7.68 (1 H, dd), 7.61 (1 H, dd), 7.53 (1 H, s), 6.45 (1 H, s), 4.49 - 4.38 (2 H, m), 4.27 (2 H, t), 4.00 (1 H, ddt), 3.90 — 3.61 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t) (1H, CDC13) 8 ppm 7.76 (1 H, d), 7.58 (1 H, dd), 7.50 (1 H, s), 6.88 — 7.03 (3 H, \1 m), 6.44 (1 H, s), 4.54 - 4.39 (2 H, m), 4.28 (2 H, t), 4.03 (1 H, m), 3.95 — 3.63 (11 H, m), 3.53 (1 H, dd), 3.08 (2 H, t) (1H, CDC13) 8 ppm 8.50 (1 H, d), 7.74 (2 H, td), 7.55 (1 H, dd), 7.45 (1 H, s), 6.75 (1 H, d), 6.40 (1 H, s), 4.56 - 4.38 (2 H, m), 4.26 (2 H, t), 4.01 (1 H, m), 3.94 - 3.58 (9 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.70 (6 H, br. s.) (1H, CDC13) 8 ppm 8.21 (1 H, dd), 7.78 (1 H, d), 7.66 (2 H, ddd), 7.56 (1 H, s), 7.01 (1 H, dd), 6.45 (1 H, s), 4.54 - 4.39 (4 H, m), 4.28 (2 H, t), 4.03 (1 H, m), 3.94 — 3.64 (5 H, m), 3.53 (1 H, dd), 3.09 (2 H, t), 1.42 (3 H, t) (1H, CDC13) 8 ppm 7.75 (1 H, d), 7.64 (1 H, d), 7.60 (1 H, dd), 7.52 (1 H, d), 6.47 (1 H, d), 6.43 (1 H, s), 4.53 — 4.39 (2 H, m), 4.33 — 4.23 (2 H, m), 4.03 (6 H, d), 3.94 — 3.64 (5 H, m), 3.59 — 3.48 (2 H, m), 3.08 (2 H, t) (1H, CDC13) 8 ppm 9.00 (1 H, s), 8.87 (1 H, d), 7.87 (1 H, d), 7.63 (1 H, dd), 7.56 \l ,_1 (1 H, s), 7.52 — 7.48 (1 H, m), 6.45 (1 H, s), 4.51 - 4.36 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, ddt), 3.90 — 3.60 (5 H, m), 3.54 - 3.44 (1 H, m), 3.12 (2 H, t) (1H, CDC13) 8 ppm 7.65 (1 H, d), 7.34 (1 H, d), 7.30 (1 H, s), 6.36 (1 H, s), 4.48 (2 \1 H, s), 4.46 - 4.34 (2 H, m), 4.18 (2 H, t), 4.02 — 3.92 (1 H, m), 3.89 — 3.60 (5 H, m), 3.54 — 3.42 (1 H, m), 3.00 (2 H, t), 1.30 (9 H, s) (1H, CDC13) 8 ppm 8.19 (1 H, dd), 7.69 (1 H, d), 7.38 (2 H, ddd), 7.29 (1 H, d), 6.72 (1 H, dd), 6.40 (1 H, s), 4.47 — 4.37 (2 H, m), 4.24 (2 H, t), 4.03 - 3.93 (1 H, m), 3.89 — 3.59 (5 H, m), 3.49 (1 H, t), 3.18 — 3.08 (4 H, m), 3.04 (2 H, t), 1.82 - 1.72 (4 H, m) (1H, CDC13) 8 ppm 8.51 (1 H, d), 7.75 (2 H, td), 7.56 (1 H, dd), 7.46 (1 H, s), 6.48 (1 H, d), 6.41 (1 H, s), 4.56 - 4.37 (2 H, m), 4.27 (2 H, t), 4.02 (1 H, dd), 3.95 — 3.63 (5 H, m), 3.61 — 3.45 (5 H, m), 3.09 (2 H, t), 2.14 - 1.99 (4 H, m) (1H, CDC13) 8 ppm 7.70 — 7.57 (2 H, m), 7.47 — 7.20 (5 H, m), 7.05 (1 H, dd), 6.96 \1 LI] (1 H, d), 6.27 (1 H, s), 5.26 (2 H, s), 4.47 - 4.32 (2 H, m), 4.23 - 4.15 (2 H, m), 4.03 — 3.91 (1 H, m), 3.89 — 3.56 (5 H, m), 3.47 (1 H, dd), 2.97 (2 H, t) de# NMR data (8) (1H, CDC13) 5 ppm 7.67 (1 H, d), 7.05 (1 H, dd), 6.96 (1 H, d), 6.75 (1 H, s), 6.31 (1 H, s), 5.18 (2 H, s), 4.53 - 4.34 (2 H, m), 4.22 (2 H, t), 4.00 (1 H, m), 3.92 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.00 (2 H, t), 1.32 (9 H, s) (1H, CDC13) 5 ppm 7.64 (1 H, d), 7.00 (1 H, dd), 6.91 (1 H, d), 6.27 (1 H, s), 5.17 (2 H, s), 4.47 - 4.32 (2 H, m), 4.23 - 4.14 (2 H, m), 3.96 (1 H, qd), 3.89 — 3.58 (5 H, m), 3.47 (1 H, dd), 2.97 (2 H, t), 2.29 - 2.17 (1 H, m), 1.30 4 H, m) (1H, CDC13) 5 ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.92 (1 H, d), 6.27 (1 H, s), 5.22 \l 00 (2 H, s), 4.47 - 4.30 (2 H, m), 4.24 — 4.13 (2 H, m), 3.96 (1 H, m), 3.90 — 3.580 (5 H, m), 3.47 (1 H, dd), 3.02 - 2.85 (4 H, m), 1.41 (3 H, t) (H CDC13) 5 ppm 7.68 (1 H, d), 7.05 (1 H, dd), 6.95 (1 H, d), 6.32 (1 H, s), 5.26 \l \0 (2 H, s), 4.52- 4.37 (2 H, m), 4.28 - 4.20 (2 H, m), 4.06 — 3.96 (1 H, m), 3.94 — 3.62 (5 H, m), 3.51 (1 H, dd), 3.02 (2 H, t), 2.67 (3 H, s) (1H, CDC13) 5 ppm 7.65 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.22 (2 H, s), 4.47 - 4.33 (2 H, m), 4.19 (2 H, t), 4.03 — 3.91 (1 H, m), 3.89 — 3.59 (5 H, m), 3.48 (1 H, dd), 3.26 (1 H, dt), 2.99 (2 H, t), 1.43 (6 H, d) (1H, CDC13) 5 ppm 7.63 (1 H, d), 7.40 (1 H, dd), 7.34 (1 H, s), 6.38 (1 H, s), 4.53 — 4.37 (2 H, m), 4.27 - 4.17 (2 H, m), 4.05 — 3.96 (1 H, m), 3.93 — 3.63 (5 H, m), 3.58 — 1.97 (2 H, m), 1.90 - 3.46 (1 H, m), 3.00 (2 H, t), 2.88 (1 H, m), 2.13 — 1.56 (6 H, (1H, CDC13) 5 ppm 7.64 (1 H, d), 7.41 (1 H, d), 7.35 (1 H, s), 6.38 (1 H, s), 4.52 — 00 [\J 4.36 (2 H, m), 4.22 (2 H, t), 4.01 (1 H, m), 3.93 — 3.63 (5 H, m), 3.51 (1 H, t), 3.00 (2 H, t), 2.71 - 2.58 (1 H, m), 1.99 - 1.31 (10 H, m) (H CDC13) 5 ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.49 — 00 DJ 4.40 (2 H, m), 4.22 (2 H, t), 4.05 - 3.97 (1 H, m), 3.91 — 3.65 (5 H, m), 3.51 (1 H, dd), 3.00 (2 H, t), 2.88 — 2.78 (1 H, m), 1.31 (6 H, d) (1H, CDC13) 5 ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.51 — 4.38 (2 H, m), 4.26 - 4.18 (2 H, m), 4.07 — 3.97 (1 H, m), 3.93 — 3.64 (5 H, m), 3.52 (1 H, dd), 3.00 (2 H, t), 2.47 (2 H, t), 1.70 — 1.45 (4 H, m), 0.99 (3 H, t) (1H, CDC13) 5 ppm 7.65 (1 H, d), 7.45 (1 H, dd), 7.41 — 7.31 (5 H, m), 7.27 (1 H, s), 6.37 (1 H, s), 4.49 — 4.34 (2 H, m), 4.24 - 4.17 (2 H, m), 4.02 - 3.94 (1 H, m), 3.90 — 3.60 (7 H, m), 3.54 (2 H, s), 3.52 — 3.45 (1 H, m), 3.00 (2 H, t), 2.42 (3 H, s) (1H, CDC13) 5 ppm 7.63 (1 H, d), 7.42 (1 H, dd), 7.36 (1 H, s), 6.37 (1 H, s), 4.70 — 4.65 (1 H, m), 4.47 - 4.37 (2 H, m), 4.20 (2 H, t), 400—397 (1 H, m), 3.88 — 3.63 (5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.93 — 0.97 (6 H, m) — 1.65 (4 H, m), 1.00 de# NMR data (8) (1H, CDC13) 8 ppm 7.63 (1 H, d), 7.42 (1 H, d), 7.36 (1 H, s), 6.37 (1 H, s), 4.80 — 4.77 (1 H, m), 4.46 - 4.37 (2 H, m), 4.20 (2 H, t), 401—397 (1 H, m), 3.89 — 3.65 (5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.99 (1 H, d), 1.57 (3 H, d) (1H, CDC13) 8 ppm 7.60 (1 H, d), 7.07 (1 H, d), 6.99 (1 H, s), 6.35 (1 H, s), 4.49 — 4.38 (2 H, m), 4.21 (2 H, t), 4.01 (1 H, m), 3.94 - 3.62 (5 H, m), 3.51 (1 H, t), 2.99 (2 H, t), 2.07 - 1.86 (1 H, m), 1.15 — 1.06 (2 H, m), 0.85 — 0.78 (2 H, m) (1H, DMSO-d6) 8 ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H, s), .53 (1 H, d), 4.43 - 4.41 (1 H, m), 4.26 - 4.25 (2 H, m), 4.01 (2 H, t), 3.87 — 3.40 (7 H, m), 3.00 (2 H, t), 1.67 — 1.65 (2 H, m), 0.98 (3 H, t) (1H, 6) 8 ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H, s), .53 (1 H, d), 4.28 — 4.25 (3 H, m), 4.01 (2 H, t), 3.85 — 3.38 (7 H, m), 3.00 (2 H, t), 1.85 — 1.80 (1 H, m), 0.98 (6 H, t) (1H, DMSO-d6) 8 ppm 8.00 (1 H, d), 7.44 (1 H, s), 7.38 (1 H, d), 6.68 (1 H, s), .27 (1 H, S), 4.26 - 4.25 (2 H, m), 4.01 (2 H, t), 3.86 — 3.74 (3 H, m), 3.67 — 3.60 (2 H, m) 3.52 — 3.46 (1 H, m), 3.37 — 3.35 (1 H, m), 3.00 (2 H, t), 1.66 — 1.62 (4 H, m), 0.99 (6 H, t) (1H, CDC13) 8 ppm 7.71 (2 H, d), 7.66 (1 H, d), 7.47 (1 H, d), 7.43 — 7.32 (4 H, m), \o [\J 6.38 (1 H, s), 4.47 — 4.37 (2 H, m), 4.20 (2 H, t), 4.00 — 3.98 (1 H, m), 3.97 — 3.68 (5 H, m), 3.49 (1 H, t), 3.00 (2 H, t), 2.53 (1 H, s), 1.88 (3 H, s) (H, CDC13) 8 ppm 7.64 (1 H, d), 7.43 — 7.29 (7 H, m), 6.37 (1 H, s), 4.46 — 4.37 (2 6 DJ H, m), 4.21 (2 H, t), 3.99 — 3.95 (3 H, m), 3.88 — 3.63 (7 H, m), 3.49 (1 H, t), 2.99 (2 H, t) (1H, CDC13) 8 ppm 7.57 — 7.48 (1 H, d), 7.38 (1 H, s), 6.68 — 6.55 (1 H, d), 6.49 (1 H, s), 6.35 (1 H, s), 6.28 (1 H, s), 6.20 (1 H, s), 4.60 — 4.50 (1 H, m), 4.38 — 4.30 (4 H, m), 4.22 - 4.15 (2 H, m), 4.03 — 3.93 (1 H, m), 3.95 — 3.60 (5 H, m), 3.55 —3.40 (1 H, t), 2.98 - 2.85 (2 H, m) (1H, CDC13) 8 ppm 7.86 (1 H, s), 7.77 (1 H, s), 7.70 (1 H, d), 7.51 (1 H, d), 7.42 (1 6 LI] H, s), 6.39 (1 H, s), 4.51 — 4.37 (2 H, m), 4.330 — 4.20 (4 H, m), 4.05 — 3.96 (1 H, m), 3.87 (5 H, s), 3.51 (1 H, dd), 3.05 (2 H, t), 1.57 (4 H, t) (1H, CDC13) 8 ppm 7.85 (1 H, s), 7.75 (1 H, s), 7.70 (1 H, d), 7.50 (1 H, dd), 7.42 (1 H, s), 6.39 (1 H, s), 4.50 — 4.39 (2 H, m), 4.27 — 4.18 (4 H, m), 4.05 — 3.97 (1 H, m), 3.86 (5 H, m), 3.51 (1 H, dd), 3.05 (2 H, t), 1.88 — 1.79 (2 H, m), 1.69 — 1.59 (1 H, m), 1.00 (6 H, d) WO 92791 de# NMR data (8) (1H, CDC13) 5 ppm 8.03 (1 H, d), 7.67 — 7.63 (2 H, m), 7.05 (1 H, d), 6.65 (1 H, s), \o \1 6.28 (1 H, dd), 4.30 — 4.23 (2 H, m), 4.04 (2 H, t), 3.89 — 3.75 (3 H, m), 3.63 (2 H, dd), 3.50 (1 H, d), 3.39 (1 H, dd), 3.04 (2 H, t), 2.37 (3 H, s) (1H, CDC13) 5 ppm 7.64 (1 H, d), 7.42 (1 H, d), 7.36 (1 H,s), 6.37 (1 H, s), 4.66 — 4.61 (1 H, m), 4.47 - 4.37 (2 H, t), 4.20 (2 H, t), 4.00 — 3.88 (1 H, m), 3.88 — 3.46 (5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.90 - 1.89 (1 H, m), 1.81 - 1.77 (2 H, m), 1.57 — 1.54 (2 H, m), 1.00 (3 H, t) (1H, CDC13) 5 ppm 7.75 (1 H, d), 7.33 — 7.28 (1 H, m), 7.22 (1 H, s), 6.41 (1 H, s), 4.50 — 4.39 (2 H, m), 4.29 — 4.23 (2 H, m), 4.05 — 3.97 (1 H, m), 3.85 (5 H, m), 3.54 — 3.47 (1 H, m), 3.07 (2 H, d), 2.36 (6 H, s) (1H, CDC13) 5 ppm 8.36 (1 H, br. s.), 8.07 (1 H, br. s.), 7.99 (1 H, d), 7.64 — 7.70 (2 H, m), 6.65 (1 H, s), 4.31 - 4.22 (2 H, m), 4.05 (2 H, t), 3.90 — 3.84 (1 H, m), 3.79 (2 H, td), 3.70 — 3.57 (2 H, m), 3.51 — 3.50 (1 H, m), 3.55 — 3.45 (1 H, m), 3.39 (1 H, dd), 3.01 (2 H, t) (1H, CDC13) 5 ppm 7.85 (1 H, d), 7.74 (1 H, d), 7.70 (1 H, d), 7.50 (1 H, dd), 7.44 — 7.38 (1 H, m), 6.38 (1 H, s), 4.48 — 4.348 (2 H, m), 4.27 - 4.17 (2 H, m), 4.15 (2 H, t), 4.04 — 3.96 (1 H, m), 3.90 — 3.64 (5 H, m), 3.50 (1 H, dd), 3.04 (2 H, t), 2.02 — 1.90 (2 H, m), 0.97 (3 H, t) (1H, CDC13) 5 ppm 7.91 — 7.80 (2 H, m), 7.71 (1 H, dd), 7.62 — 7.45 (4 H, m), 6.45 (1 H, s), 4.49 - 4.39 (2 H, m), 4.27 (2 H, t), 4.06 — 3.94 (1 H, m), 3.92 — 3.61 (5 H, m), 3.51 (1 H, dd), 3.11 (2 H, t) (1H, CDC13) 5 ppm 7.80 — 7.90 (2 H, m), 7.79 — 7.69 (1 H, m), 7.66 — 7.51 (4 H, m), 6.47 (1 H, s), 4.57 - 4.41 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 — 3.64 (5 H, m), 3.53 (1 H, t), 3.14 (2 H, t) (1H, CDC13) 5 ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.91 (1 H, d), 6.28 (1 H, s), 5.18 (2 H, s), 4.47 - 4.35 (2 H, m), 4.24 - 4.15 (2 H, m), 4.02 — 3.93 (1 H, m), 3.89 — 3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t), 2.29 - 2.18 (1 H, m), 1.33 - 1.20 (4 H, (1H, CDC13) 5 ppm 7.65 (1 H, s), 7.51 — 7.46 (1 H, m), 7.45 — 7.41 (1 H, m), 6.37 (1 H, s), 4.49 - 4.36 (2 H, m), 4.21 (2 H, s), 4.04 — 3.94 (1 H, m), 3.90 — 3.610 (5 H, m), 3.53 — 3.44 (1 H, m), 3.25 (1 H, s), 3.00 (2 H, s) (1H, CDC13) 5 ppm 9.18 (1 H, s), 8.88 (2 H, s), 7.72 (1 H, d), 7.60 — 7.53 (1 H, m), 7.51 (1 H, d), 6.40 (1 H, s), 4.49 — 4.36 (2 H, m), 4.23 (2 H, t), 4.02 - 3.95 (1 H, m), 3.89 — 3.58 (5 H, m), 3.49 (1 H, dd), 3.04 (2 H, t) 2012/076275 de# NMR data (8) (1H, CDC13) 5 ppm: 7.54 (1 H, d), 7.37 (1 H, dd), 7.32 (1 H,s), 7.26 — 7.22 (2 H, 107 m), 6.81 (1 H, t), 6.75 (2 H, dd), 6.35 (1 H, s), 4.46 — 4.36 (2 H, m), 4.20 - 4.17 (4 H, m), 4.00 — 3.91 (1 H, m), 3.88 — 3.63 (5 H, m), 3.49 (1 H, t), 2.97 (2 H, t) (1H, CDC13) 5 ppm 8.36 (1 H, d), 7.89 — 7.65 (3 H, m), 7.62 — 7.55 (3 H, m), 6.44 (1 H, s), 4.51 - 4.38 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m), 3.91 — 3.62 (5 H, m), 3.50 (1 H, dd), 3.22 — 3.14 (1 H, m), 3.09 (2 H, t), 1.40 (1 H, t) (1H, CDC13) 5 ppm 7.70 — 7.60 (1 H, d), 7.50 — 7.42 (1 H, d), 7.39 (1 H, s), 6.37 (1 H, s), 4.50 - 4.35 (2 H, m), 4.25 — 4.15 (2 H, m), 4.05 — 3.95 (2 H, m), 3.92 — 3.60 (5 H, m), 3.56 — 3.45 (4 H, m), 3.05 — 3.95 (2 H, m), 2.15 - 1.95 (1 H, m), 1.15 -1 (6 HA) (1H, CDC13) 5 ppm 7.58 (1 H, d), 7.33 (1 H, d), 7.27 (1 H, s), 6.32 (1 H, s), 4.45 — 4.34 (2 H, m), 4.17 (2 H, t), 3.96 (1 H, qd), 3.86 — 3.60 (5 H, m), 3.46 (1 H, dd), 2.94 (2 H, t), 1.46 (1 H, tt), 0.94 — 0.86 (2 H, m), 0.86 — 0.79 (2 H, m) (1H, CDC13) 5 ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, s), 4.48 - 4.34 (2 H, m), 4.19 (2 H, t), 4.02 - 3.93 (1 H, m), 3.89 — 3.60 (5 H, m), 3.48 (1 H, t), 3.43 — 3.35 (1 H, m), 2.98 (2 H, t), 2.95 - 2.85 (1 H, m), 2.76 - 2.64 (1 H, m), 1.84 - 1.62 (3 H, m), 0.92 (6 H, dd) (1H, CDC13) 5 ppm 7.67 (1 H, d), 7.44 (1 H, d), 7.39 (1 H, s), 6.38 (1 H, s), 5.00 (2 H, s), 4.50 - 4.36 (2 H, m), 4.21 (2 H, t), 4.03 — 3.95 (1 H, m), 3.91 — 3.61 (5 H, m), 3.49 (1 H, dd), 3.01 (2 H, t) (1H, CDC13) 5 ppm 7.64 - 7.58 (1 H, m), 7.24 — 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.25 — 4.17 (2 H, m), 4.03 — 3.95 (1 H, m), 3.90 — 3.61 (5 H, m), 3.54 — 3.45(1 H, m), 3.02 — 2.95 (2 H, m), 2.81 - 2.72 (2 H, m), 1.59 — 1.49 (2 H, m), 0.77 — 0.64 (1 H, m), 0.49 - 0.42 (2 H, m), 0.10 - 0.02 (2 H, m) (1H, CDC13) 5 ppm 7.66 (1 H, d), 7.33 (1 H, d), 7.29 (1 H, s), 6.36 (1 H, s), 4.50 (2 H, s), 4.47 - 4.35(2 H, m), 4.19 (2 H, t), 4.07 — 3.93 (2 H, m), 3.90 — 3.60 (5 H, m), 3.48 (1 H, t), 3.00 (2 H, t), 1.82 - 1.70 (6 H, m), 1.62 - 1.50 (2 H, m) (1H, CDC13) 5 ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, s), 6.28 (1 H, s), 6.11 — 6.01 (1 H, m), 5.45 (1 H, dd), 5.34 (1 H, dd), 4.61 (2 H, dd), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.03 — 3.95 (1 H, m), 3.89 — 3.64 (5 H, m), 3.49 (1 H, t), 2.98 (2 H, t) (1H, CDC13)6 ppm 7.63 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, d), 6.28 (1 H, s), 6.11 — 6.01 (1 H, m), 5.44 (1 H, m), 5.34 (1 H, dd), 4.61 (2 H, dt), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.03 — 3.95 (1 H, m), 3.89 — 3.63 (5 H, m), 3.49 (1 H, dd), 2.98 (2 H, WO 92791 de# NMR data (8) (1H, CDC13) 5 ppm 7.68 (1 H, d), 7.36 (1 H, d), 7.31 (1 H, s), 6.41 — 6.38 (1 H, m), 4.61 (2 H, s), 4.47 - 4.37 (2 H, m), 4.25 — 4.17 (2 H, m), 3.99 (3 H, dt), 3.89 — 3.60 (6 H, m), 3.53 — 1.94 (2 H, m), 1.74 — 3.43 (3 H, m), 3.02 (2 H, t), 2.01 - 1.64 (2 H, (1H, CDC13) 5 ppm 8.62 (1 H, br. s.), 8.53 (1 H, br. s.), 7.73 (1 H, d), 7.64 (1 H, d), 7.41 (1 H, dd), 7.35 (1 H, s), 7.29 (1 H, d), 6.36 (1 H, s), 4.48 - 4.34 (2 H, m), 4.20 (2 H, t), 4.03 — 3.93 (3 H, m), 3.89 — 3.61 (7 H, m), 3.48 (1 H, dd), 2.99 (2 H, t) (1H, CDC13) 5 ppm 7.60 (1 H, d), 7.19 (1 H, dd), 7.10 (1 H, s), 6.34 (1 H, s), 4.49 - 4.34 (2 H, m), 4.20 (2 H, t), 4.02 - 3.93 (1 H, m), 3.90 - 3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t), 2.64 (2 H, t), 1.63 (2 H, m), 1.37 - 1.29 (4 H, m), 0.94 - 0.86 (3 H, m) (1H, CDC13) 5 ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H, s), 4.50 - 4.39 (2 H, m), 4.20 (2 H, t), 4.02 — 3.98 (1 H, m), 3.89 — 3.66 (5 H, m), 3.49 (1 H, t), 2.96 (2 H, t), 1.59 - 1.48 (1 H, m), 0.98 — 0.81 (4 H, m) (1H, CDC13) 5 ppm 7.64 — 7.58 (1 H, m), 7.24 — 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.24 - 4.17 (2 H, m), 4.03 — 3.95 (1 H, m), 3.91 — 3.62 (5 H, m), 3.49 (1 H, dd), 3.03 — 2.95 (2 H, m), 2.81 — 2.73 (2 H, m), 1.59 — 1.50 (2 H, m), 0.71 (1 H, s), 0.49 — 0.42 (2 H, m), 0.09 — 0.03 (2 H, m) (1H, CDC13) 5 ppm 7.69 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.82 — 4.75 (2 H, m), 4.72 - 4.64 (3 H, m), 4.49 (2 H, s), 4.48 - 4.37 (2 H, m), 4.21 (2 H, dd), 4.03 — 3.95 (1 H, m), 3.90 — 3.62 (5 H, m), 3.49 (1 H, dd), 3.02 (2 H, t) (1H, CDC13) 5 ppm 7.69 (1 H, d), 7.35 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.62 (2 H, s), 4.54 (2 H, d), 4.48 - 4.36 (4 H, m), 4.21 (2 H, t), 3.99 (1 H, ddt), 3.90 — 3.61 (5 H, m), 3.58 (2 H, s), 3.49 (1 H, dd), 3.02 (2 H, t), 1.36 (3 H, s) (1H, CDC13) 5 ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48 (1 H, s), 6.21 (1 H, s), 4.47 — 4.34 (2 H, m), 4.21 - 4.14 (2 H, m), 4.01 - 3.91 (1 H, m), 3.89 — 3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, s), 2.90 (2 H, t), 1.36 (2 H, dd), 0.96 (6 H, s), 0.87 (3 H, t) (1H, CDC13) 5 ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, d), 4.46 - 4.34 (2 H, m), 4.19 (2 H, t), 3.97 (1 H, td), 3.89 — 3.60 (5 H, m), 3.48 (1 H, t), 3.42 — 3.35 (1 H, m), 2.97 (2 H, t), 2.93 — 2.85 (2 H, m), 2.70 (1 H, m), 1.84 — 1.63 (3 H, m), 0.92 (6 H, dd) (1H, CDC13) 5 ppm 7.51 (1 H, d), 6.63 (1 H, d), 6.49 (1 H, br. s.), 6.21 (1 H, s), 4.46 - 4.356 (2 H, m), 4.21 - 4.11 (2 H, m), 3.97 (1 H, ddt), 3.88 — 3.62 (5 H, m), 3.48 (1 H, dd), 3.10 (2 H, d), 2.91 (2 H, t), 1.61 (1 H, m), 1.47 - 1.26 (8 H, m), 0.97 — 0.88 (6 H, m) WO 92791 de# NMR data (8) (1H, CDC13) 5 ppm 7.63 (1 H, d), 6.93 (1 H, dd), 6.82 (1 H, d), 6.29 (1 H, s), 5.30 (1 H, s), 4.47 — 4.36 (2 H, m), 4.22 - 4.14 (4 H, m), 4.03 — 3.94 (1 H, m), 3.88 — 3.628 (7 H, m), 3.53 — 3.453 (4 H, m), 2.97 (2 H, t) (1H, CDC13) 5 ppm 7.64 — 7.58 (1 H, m), 6.90 (1 H, dd), 6.80 (1 H, d), 6.29 — 6.24 (1 H, m), 4.46 - 4.32 (2 H, m), 4.22 - 4.12 (4 H, m), 4.01 — 3.90 (1 H, m), 3.88 — 3.54 (9 H, m), 3.46 (1 H, dd), 2.95 (2 H, s), 1.23 (3 H, t) (1H, CDC13) 5 ppm 7.60 — 7.67 (1 H, m), 6.93 — 6.86 (1 H, m), 6.78 (1 H, d), 6.29 (1 H, s), 4.50 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.94 (1 H, m), 3.91 - 3.61 (7 H, m), 3.53 — 3.44 (1 H, m), 3.01 - 2.93 (2 H, m), 1.37 - 1.227 (1 H, m), 0.73 — 0.65 (2 H, m), 0.42 - 0.34 (2 H, m) (1H, CDC13) 5 ppm 7.64 (1 H, d), 6.93 (1 H, s), 6.82 (1 H, d), 6.27 (1 H, s), 4.90 — 4.82 (1 H, m), 4.74 - 4.67 (1 H, m), 4.48 - 4.28 (3 H, m), 4.26 - 4.14 (3 H, m), 4.03 — 3.91 (1 H, m), 3.90 — 3.58 (5 H, m), 3.53 — 3.41 (1 H, m), 3.03 - 2.91 (2 H, m) (1H, CDC13) 5 ppm 7.64 (1 H, s), 7.48 — 7.40 (1 H, m), 7.40 — 7.35 (1 H, m), 6.40 — 6.34 (1 H, m), 4.47 (4 H, s), 4.28 — 4.15 (1 H, m), 3.93 — 3.56 (10 H, m), 3.43 (5 H, s), 3.06 — 2.95 (2 H, m) (1H, CDC13) 5 ppm 7.65 (1 H, d), 7.47 — 7.41 (1 H, m), 7.38 (1 H, s), 6.37 (1 H, s), 4.37 — 4.49 (4 H, m), 4.26 - 4.17 (2 H, m), 3.99 (1 H, m), 3.93 - 3.44 (12 H, m), 3.05 — 2.94 (2 H, m), 1.25 (3 H, t) (1H, CDC13) 5 ppm 7.66 (1 H, d), 7.47 — 7.42 (1 H, m), 7.40 (1 H, s), 6.37 (1 H, s), 4.73 — 4.67 (1 H, m), 4.62 - 4.54 (1 H, m), 4.49 (4 H, s), 4.26 - 4.16 (2 H, m), 4.04 — 3.95 (1 H, m), 3.94 — 3.60 (7 H, m), 3.56 — 3.43 (1 H, m), 3.05 — 2.96 (2 H, m) (1H, CDC13) 5 ppm 7.68 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.57 (2 H, s), 4.50 - 4.36 (2 H, m), 4.27 — 4.17 (2 H, m), 4.06 — 3.92 (1 H, m), 3.92 — 3.60 (5 H, m), 3.57 — 3.44 (1 H, m), 3.17 (2 H, s), 3.09 — 2.96 (2 H, m), 0.97 (9 H, s) (1H, CDC13) 5 ppm 7.70 — 7.64 (1 H, m), 7.40 — 7.33 (1 H, m), 7.31 (1 H, s), 6.37 (1 H, s), 4.59 (2 H, s), 4.50 — 4.35 (2 H, m), 4.27 - 4.16 (2 H, m), 4.07 - 3.94 (1 H, m), 3.93— 3.59 (5 H, m), 3.57 — 3.44 (1 H, m), 3.45 — 3.34 (1 H, m), 3.08 — 2.96 (2 H, m), 2.05 - 1.90 (2 H, m), 1.82 - 1.71 (2 H, m), 1.48 - 1.18 (6 H, m) (1H, CDC13) 5 ppm 7.68 (1 H, d), 7.37 (1 H, d), 7.32 (1 H, s), 6.38 (1 H, s), 4.58 (2 H, s), 4.51 - 4.36 (2 H, m), 4.26 — 4.176 (2 H, m), 4.05 — 3.94 (1 H, m), 3.92 — 3.61 (5 H, m), 3.54 — 3.44 (1 H, m), 3.38 (2 H, d), 3.07 — 2.98 (2 H, m), 1.20 — 1.05 (1 H, m), 0.63 — 0.54 (2 H, m), 0.29 - 0.20 (2 H, m) 2012/076275 de# NMR data (8) (1H, CDC13) 5 ppm 7.62 (1 H, s), 6.91 (1 H, m), 6.81 (1 H, m), 6.27 (1 H, s), 4.41 139 (2 H, s), 4.25 — 1.84 (1 — 4.21 (2 H, m), 4.10 _ 3.41 (12 H, m), 2.96 (2 H, t), 2.01 H, m), 1.76 — 1.36 (5 H, m) (1H, DMSO-d6) 5ppm 7.91 (1 H, d), 7.28 — 7.18 (2 H, m), 6.60 (1 H, s), 4.32 — 4.17 (2 H, m), 4.07 — 3.96 (2 H, m), 3.92 — 3.71 (3 H, m), 3.70 — 3.43 (4 H, m), 3.38 (2 H, m), 3.03 — 2.91 (2 H, m), 2.78 — 2.58 (2 H, m), 1.68 — 1.58 (2 H, m), 1.08 (3 H, (1H, CDC13) 5 ppm 7.70 — 7.58 (1 H, d), 6.95 — 6.82 ( 1 H, d), 6.77 (1 H, s), 6.27 (1 H, s), 4.50 - 4.32 (2 H, m), 4.38- 4.15 (2 H, m), 4.05 — 3.92 (3 H, m), 3.92 — 3.60 (5 H, m), 3.55 — 3.42 (1 H, t), 3.05 — 2.92 (2 H, m), 1.85 - 1.70 (2 H, m), 1.40 - 1.30 (2 H, m), 0.92 (9 H, s) (1H, CDC13) 5 ppm 7.61 (1 H, d), 7.21 (1 H, d), 7.13 (1 H, s) 6.35 (1 H, s), 4.46 — 4.40 (2 H, m), 4.20 (2 H, t), 3.99 — 3.97 (1 H, m), 3.87 — 3.65 (5 H, m), 3.49(1 H, t), 3.39 (3 H, s), 3.00 — 2.93 (3 H, m), 2.83 — 2.82 (1 H, m), 2.66 - 2.64 (1 H, m), 1.95 — 1.91 (1 H, m), 1.75 — 1.73 (2 H, m), 0.90 (6 H, t) (1H, CDC13) 5 ppm 7.66 — 7.60 (1 H, m), 6.91 — 6.86 (1 H, m), 6.80 — 6.76 (1 H, m), 6.28 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.17 (2 H, m), 4.11 - 4.04 (2 H, m), 4.02 — 3.95 (1 H, m), 3.91 — 3.61 (5 H, m), 3.54 — 3.45 (1 H, m), 3.03 - 2.94 (2 H, m), 1.98 — 1.88 (2 H, m), 1.45 — 1.36 (2 H, m), 0.78 — 0.66 (1 H, m), 0.50 — 0.43 (2 H, m), 0.09 — 0.03 (2 H, m) (1H, CDC13) 5 ppm 7.47 (1 H, d), 6.55 — 6.48 (1 H, m), 6.40 — 6.34 (1 H, m), 6.18 (1 H, s), 4.47 - 4.33 (2 H, m), 4.22 - 4.12 (2 H, m), 4.02 - 3.92 (1 H, m), 3.83 (5 H, dd), 3.53 — 3.43 (1 H, m), 3.40 — 3.28 (1 H, m), 2.89 (2 H, t), 2.13 - 1.98 (2 H, m), 1.86 — 1.73 (2 H, m), 1.73 — 1.63 (1 H, m), 1.50 - 1.11 (5 H, m) (1H, DMSO-d6) 5 ppm 7.95 — 7.87 (1 H, m), 7.29 — 7.19 (2 H, m), 6.60 (1 H, s), 4.54 - 4.44 (1 H, m), 4.29 - 4.21 (2 H, m), 4.07 — 3.97 (2 H, m), 3.91 — 3.72 (3 H, m), 3.70 — 3.54 (2 H, m), 3.54 — 3.43 (1 H, m), 3.43 — 3.34(1 H, m), 3.06 — 2.81 (4 H, m), 2.63 - 2.52 (1 H, m), 1.81 - 1.64 (1 H, m), 1.52 - 1.36 (1 H, m), 0.81 (9 H, (H, CDC13) 5 ppm 7.68 (1 H, d), 7.38 — 7.32 (1 H, m), 7.30 (1 H, s), 6.38 (1 H, s), 4.56 (2 H, s), 4.50 — 4.36 (2 H, m), 4.26 - 4.18 (2 H, m), 4.04 - 3.94 (1 H, m), 3.94 — 3.5994 (4 H, m), 3.55 — 3.44 (1 H, m), 3.40 (2 H, d), 3.07 — 2.98 (2 H, m), 2.30 — 2.16 (1 H, m), 1.86 - 1.72 (2 H, m), 1.66 - 1.51 (5 H, m), 1.35 - 1.20 (2 H, m) (1H, CDC13) 5 ppm 7.61 (1 H, d), 7.18 (1 H, dd), 7.12 (1 H, d), 6.35 (1 H, s), 4.46 - 4.36 (2 H, m), 4.21 (2 H, t), 4.00 — 3.97 (1 H, m), 3.88 — 3.64 (5 H, m), 3.49 (1 H, t), 3.34 — 3.30 (4 H, m), 2.98 (2 H, t), 2.81 — 2.60 (2 H, m), 1.89 - 1.676 (2 H, m), 1meHm WO 92791 de# NMR data (8) (1H, CDC13) 8 ppm: 7.62 (1 H, d), 7.23 — 7.13 (4 H, m), 6.71 (1 H, t), 6.58 (2 H, d), 6.12 (1 H, s), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.08 — 3.98 (1 H, m), 3.88 — 3.63 (6 H, m), 3.49 (1 H, t), 3.17 (2 H, t), 2.98 (2 H, t), 2.79 (2 H, t), 2.01 - 1.94 (2 H, (1H, CDC13) 8 ppm 7.61 (1 H, d), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47 — 4.37 (2 H, m), 4.21 (2 H, t), 4.01 — 3.97 (1 H, m), 3.88 — 3.63 (6 H, m), 3.49 (1 H, t), 2.98 (2 H, t), 2.69 (2 H, t), 1.89 - 1.62 (2 H, m), 1.52 -145 (2 H, m), 1.31 - 1.30 (1 H, m), 1.20 (3 H, d) (1H, CDC13) 8 ppm 7.61 (1 H, d), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47 — 4.37 (2 H, m), 4.21 (2 H, t), 4.01 — 3.97 (1 H, m), 3.88 — 3.63 (7 H, m), 3.49 (1 H, t), 2.98 (2 H, t), 2.70 (2 H, t), 1.76 - 1.60 (4 H, m), 1.31 - 1.26 (1 H, m) (1H, CDC13) 8 ppm 7.57 — 7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H, ), 4.513 - 4.33 (2 H, m), 4.26 — 4.14 (2 H, m), 4.06 — 3.93 (1 H, m), 3.92 — 3.56 (6 H, m), 3.56 — 3.41 (1 H, m), 3.00 — 2.90 (2 H, m), 2.88 (3 H, s), 2.04 — 1.63 (2 H, m), 1.60 — 1.31 (5 H, m), 1.28 - 1.08 (1 H, m) (1H, CDC13) 8 ppm 7.52 — 7.46 (1 H, m), 6.55 — 6.50 (1 H, m), 6.40 — 6.36 (1 H, m), 6.19 (1 H, s), 4.48 - 4.33 (2 H, m), 4.23 — 4.13 (2 H, m), 4.04 — 3.92 (1 H, m), 3.85 (5 H, d), 3.56 — 3.42 (1 H, m), 3.06 — 2.99 (2 H, m), 2.93 - 2.84 (2 H, m), 1.92 - 1.50 (6 H, m), 1.36 — 1.12 (3 H, m), 1.08 - 0.91 (2 H, m) (1H, CDC13) 8 ppm 7.50 (1 H, d), 6.59 — 6.49 (1 H, m), 6.44 — 6.35 (1 H, m), 6.20 (1 H, s), 4.49 - 4.33 (2 H, m), 4.24 - 4.13 (2 H, m), 4.05 — 3.93 (3 H, m), 3.92 — 3.59 (5 H, m), 3.56 — 3.32 (3 H, m), 3.16 — 3.07 (2 H, m), 2.96 — 2.84 (2 H, m), 1.98 — 1.80 (1 H, m), 1.79 - 1.64 (2 H, m), 1.428 - 1.28 (2 H, m) (1H, CDC13) 8 ppm 7.54 — 7.46 (1 H, m), 7.14 — 7.08 (1 H, m), 7.04 (1 H, s), 6.23 (1 H, s), 4.35 - 4.21 (2 H, m), 4.13 — 3.99 (2 H, m), 3.91 — 3.80 (1 H, m), 3.79 — 3.45 (5 H, m), 3.41 — 3.30 (1 H, m), 2.86 (2 H, t), 2.64 — 2.54 (2 H, m), 1.67 — 1.58 (2 H, m), 1.45 (4 H, d), 0.80 (6 H, m) (1H, CDC13) 8 ppm 7.60 (1 H, d), 7.23 — 7.19 (1 H, m), 7.13 (1 H, s), 6.34 (1 H, s), 4.45 - 4.35 (2 H, m), 4.18 (2 H, t), 4.02 - 3.92 (1 H, m), 3.82 (5 H, m), 3.48 (1 H, dd), 2.97 (2 H, br. t), 2.79 — 2.70 (2 H, m), 1.82 — 1.74 (2 H, m), 1.30 (6 H, s) (1H, CDC13) 8 ppm 7.64 — 7.59 (1 H, m), 7.25 — 7.20 (1 H, m), 7.14 (1 H, s), 6.35 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.16 (2 H, m), 4.02 — 3.94 (1 H, m), 3.90 — 3.44 (7 H, m), 3.02 - 2.95 (2 H, m), 2.92 — 2.81 (1 H, m), 2.78 — 2.67 (1 H, m), 1.87 - 1.68 (2 H, m), 1.62 - 1.42 (2 H, m), 0.96 (3 H, s) WO 92791 de# NMR data (8) (1H, CDC13) 8 ppm 7.70 — 7.56 (1 H, d), 6.95 — 6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1 158 H, s), 4.50 — 4.35 (2 H, m), 4.25 - 4.10 (2 H, m), 4.05 — 3.92 (1 H, m), 3.10 — 3.57 (8 H, m), 3.55 — 3.40 (1 H, m), 3.05 — 2.90 (2 H, m), 1.05 (9H, s) (1H, CDC13) 8 ppm 7.63 (1 H, d), 6.88 (1 H, dd), 6.77 (1H, d), 6.28 (1 H, s), 4.46 — 4.36 (2 H, m), 4.20 (2 H, t), 4.05 — 3.96 (3 H, m), 3.88 — 3.65 (7 H, m), 3.51 — 3.43 (3 H, m), 2.97 (2 H, t), 2.12 - 2.01 (1 H, m), 1.78 - 1.75 (2 H, m), 1.59 - 1.42 (2 H, (1H, CDC13) 8 ppm 7.63 (1 H, d), 7.35 — 7.18 (1 H, m), 7.12 (1H, s), 6.36 (1 H, s), 4.50 - 4.35 (2 H, m), 4.28 — 4.15 (2 H, m), 4.05 — 3.95 (1 H, m), 3.95 — 3.60 (5 H, m), 3.55 — 3.42 (1 H, m), 3.05 — 2.90 (2 H, m), 2.75 — 2.60 (2 H, m), 1.80 — 1.65 (2 H, m), 1.55 - 1.48 (2 H, m), 1.22 (6 H, s) (1H, CDC13) 8 ppm 7.68 (1 H, d), 7.34 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.55 (2 H, s), 4.48 — 3.96 (3 H, m), 3.91 - 4.38 (2 H, m), 4.22 (2 H, t), 4.02 — 3.61 (5 H, m), 3.55 — 3.35 (5 H, m), 3.02 (2 H, t), 2.00 — 1.86 (1 H, m), 1.69 (2 H, dd), 1.38 (2 H, dd) (1H, CDC13) 8 ppm 7.68 — 7.62 (1 H, m), 6.95 — 6.87 (1 H, m), 6.82 — 6.77 (1 H, m), 6.29 (1 H, s), 4.51 — 4.35 (2 H, m), 4.26 - 4.17 (2 H, m), 4.05 - 3.92 (1 H, m), 3.91 — 3.60 (8 H, m), 3.55 — 3.44 (1 H, m), 3.04 - 2.94 (2 H, m) (1H, CDC13) 8 ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.81 (1 H, d), 6.29 (1H, s), 4.91 (2 H, t), 4.56 (2 H, t), 4.47 - 4.36 (2 H, m), 4.26 (2H, d), 4.21 (2 H, t), 4.00 — 3.96 (1 H, m), 3.88 — 3.63 (5 H, m), 3.51 — 3.45 (2 H, m), 2.98 (2H, t) (1H, DMSO-d6) 8 ppm 7.93 (1 H, d), 6.97 — 6.92 (2 H, m),6.53 (1 H, s), 4.24 — 4.23 (2H, m), 4.08 (2 H, t), 4.00 (2 H, t), 3.98 — 3.74 (3 H, m), 3.68 — 3.57 (2 H, m), 3.51— 3.48 (1 H, m), 3.37 (1 H, t), 2.96 (2 H, t), 1.84 — 1.80 (2 H, m), 1.36 — 1.30 (2 H, m), 0.81 — 0.63 (1 H, m), 0.42 — 0.39 (2 H, m), 0.04 — 0.02 (2 H, m) (1H, CDC13) 8 ppm 7.65 (1 H, d), 7.24 (1H, dd), 7.16 (1H, s), 6.38 (1 H, s), 4.49 — 4.40 (2 H, m), 4.24 (2 H, t), 4.02 - 4.00 (1 H, m), 3.89 — 3.66 (3 H, m), 3.52 (3 H, m), 3.43 (2 H, t), 3.38 (3 H, s), 3.02 (2H, t), 2.78 (2 H, t), 1.96 - 1.92 (2 H, m) (1H, CDC13) 8 ppm 7.61 (1 H, d), 7.23 (1H, dd), 7.15 (1H, s), 6.35 (1 H, s), 4.46 — 4.36 (2 H, m), 4.20 (2 H, t), 4.01 — 3.95 (1 H, m), 3.88 — 3.62 (5 H, m), 3.49 (1 H, t), 2.98 (2 H, t), 2.85 - 2.81 (2 H, m), 2.13 (1H, br s), 1.93 - 1.79 (4 H, m), 1.72 — 1.55 (6 H, m) (1H, CDC13) 8 ppm 7.59 (1 H, d), 7.37 (1H, dd), 7.15 (1H, s), 6.34 (1 H, s), 4.44 - 167 4.35 (2 H, m), 4.17 (2 H, t), 4.01 — 3.92 (3 H, m), 3.88 — 3.60 (7 H, m), 3.47 (1 H, t), 2.94 (2 H, t), 2.07 - 2.02 (2 H, m), 1.95-1.88 (2H, m) de# NMR data (8) (1H, CDC13) 5 ppm 7.66 (1 H, d), 7.23 (1H, dd), 7.17 (1H, s), 6.39 (1 H, s), 4.51 — 168 4.40 (2 H, m), 4.24 (2 H, t), 4.09 — 3.96 (1 H, m), 3.93— 3.65 (5 H, m), .49 (1H, m), 3.44 (2 H, t), 3.40 (3H, s), 3.02 (2 H, t), 2.79 (2 H, t), 2.00-1.89 (2H, m) (1H, CDC13)6 ppm 7.55 (1 H, d), 7.16 (1H, dd), 7.08 (1H, s), 6.29 (1 H, s), 4.41 — 4.29 (2 H, m), 4.13 (2 H, t), 3.95 — 3.86 (1 H, m), 3.81- 3.54 (5 H, m), 3.46-3.38 (1H, m), 2.91 (2 H, t), 2.78-2.72 (2H, m), 1.87-1.75 (4 H, m), 172-153 (6 H, m) (1H, CDC13) 5 ppm 7.66 (1 H, d), 6.95 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50 — 4.39 (2 H, m), 1 (4 H, m), 4.05 — 3.98 (1 H, m), 3.91— 3.65 (7 H, m), 3.55— 3.49 (3H, m), 3.00 (2 H, t), 1.71-1.62 (2 H, m), 0.96 (3 H, t) (1H, CDC13) 5 ppm 7.65 (1 H, d), 6.94 (1H, dd), 6.83 (1H, s), 6.31 (1 H, s), 4.50 — 4.39 (2 H, m), .18 (4 H, m), 4.04 — 3.97 (1 H, m), 3.91— 3.65 (8 H, m), 3.51 (1H, t), 3.00 (2 H, t), 1.23 (6 H, d) (1H, CDC13) 5 ppm 7.67 (1 H, d), 6.95 (1H, dd), 6.85 (1H, s), 6.31 (1 H, s), 4.50 — 4.40 (2 H, m), 425.421 (4 H, m), 4.05 — 3.98 (1 H, m), 3.91— 3.65 (7 H, m), 3.55— 3.49 (3H, m), 3.00 (2 H, t), .62 (2 H, m), 0.97 (3 H, t) (1H, CDC13) 5 ppm 7.65 (1 H, d), 6.94 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50 — 4.40 (2 H, m), 4.26-4.19 (4 H, m), 4.04 — 3.97 (1 H, m), 3.92— 3.65 (8 H, m), 3.52 (1H, t), 3.00 (2 H, t), 1.23 (6 H, d) (1H, CDC13) 5 ppm 7.64 (1 H, d), 7.22 (1H, dd), 7.15 (1H, s), 6.38 (1 H, s), 4.51 — 4.41 (2 H, m), 4.23 (2 H, t), 4.06 - 4.00 (1 H, m), 3.92— 3.66 (5 H, m), 3.57—3.50 (1H, m), 3.43 (2 H, t), 3.37 (3H, s), 3.01 (2 H, t), 2.71 (2 H, t), .61 (2H, m), 1.69-1.62 (2H,m) Biological Examples 1. In vitro assays 1.1. Cell based assay: GTp-yS binding assay.
[00458] The following assay can be used for determination of GPR84 activation. The [3SS]GTPyS binding assay measures the level of G protein activation following agonist occupation of a GPCR, by determining the binding of the non-hydrolysable analog [35$]GTPyS to G01 subunits.
The assay is performed in a 96 well plate where the following reagents are added. First 50 uL compound is added into the assay plate, ed by addition of 20 uL 3,3’ di indolylmethane at ECgo concentration (concentration which gives 80% of the activity of GPR84). In a last step, 30 uL of a mixture consisting of membranes-GTPyS-SpA beads is added [mixture consists of 20 ug/well membranes derived from stable cell line over expressing GPR84 (membranes are pre-incubated with 0.1 uM GDP for 15 min at WO 92791 4°C), 0.1 nM [3SS]GTPyS (Perkin Elmer, NEG030) and 0.5 mg/well PVT-WGA SpA beads (Perkin Elmer, RPNQ0001)]. All components are diluted in assay buffer containing 20mM HEPES pH 7.4; 5mM MgClZ; 250mM NaCl; 0.05% BSA; 75ug/mL saponin. ons are incubated for 90 min at room temperature followed by centrifugation at 2000 rpm during 15 min. Plates are read on a Topcount reader (Perkin Elmer) immediately after centrifugation (readout time, 1 min/well).
TABLE IV: GPR84 assa GT S IC 0 nM of selected Com ounds of the invention. na: not active * > 1001 nM ** 00 nM ***101-500 nM **** 0.01- 100 nM 0\ DJ O\O\ 0U) O\O\ 600 ii\l\] \I 4; \l \0 0000000000000000 6066600 Lh-bwt—‘06 * * de# GPR84 97 *** **** 101 *** 102 *** 103 *** 104 **** 105 *** 106 ** 107 **** 108 **** 109 **** 110 *** 111 *** 112 **** 113 *** 114 **** 115 **** 116 *** 117 *** 118 *** 119 *** 120 *** 121 **** 122 **** 123 **** 124 *** 125 ** 126 **** 127 **** * * 128 *** * * 129 *** 130 *** 131 **** 132 ** 133 *** 134 *** 135 *** 136 **** 2. Cellular assays 2.1. Human neutrophil migration assay
[00461] We have established that GPR84 ts (MCFA such as sodiumdecanoate, 33’ di indolylmethane and Embelin induce neutrophil chemo taxis and that GPR84 antagonists could block GPR84 agonist-induced chemo taxis but not IL8-induced chemotaxis, indicating that G Protein-Coupled Receptor 84 (GPR84) is an essential player in the s of phil recruitment.
The effect of agonists or antagonists for GPR84 can therefore be assayed in a neutrophil migration test. In the neutrophil migration assay, neutrophils, freshly isolated from buffy coats from human volunteers, are treated with a compound for 30 minutes. Subsequently, the neutrophils are transferred to the upper wells of a Corning HTS transwell 96 permeable support system, of which the lower wells are filled with a n solution at ECgo (concentration which gives 80% of the activity of GPR84). After 1 h of incubation, migration of the neutrophils towards embelin in the lower compartment can be quantified by ing the ATP-content of the lower wells using the ATPlite scence ATP detection assay system (Perkin Elmer, Cat. N°.: 436110). 2.1.1 Isolation ofneutrophilsfrom human bufij} coat A human buffy coat is diluted with an equal volume of ice cold DPBS. 20 mL of the diluted buffy coat is gently mixed with 4 mL of ACD buffer (140 mM citric acid, 200 mM sodium citrate and 220 mM dextrose). Then, 12 mL of the 6% dextran/0.9% NaCl solution (15 g n T2000 and 2.25 g NaCl dissolved in 250 mL H20) is added to the mixture and the samples are inverted gently up to 20 times. The total volume was transferred to a new recipient and ted at room temperature for 1 h for complete separation of the two phases to occur. The ish supernatant is then erred to a clean centrifugation tube and centrifiJged for 12 minutes at 1300 rpm and 4°C. After centrifiJgation, the supernatant is discarded and the remaining cell pellet is rapidly resuspended in 12 mL of ice-cold H20 for red blood cell lysis to occur. After 20 seconds, 4 mL of ice-cold 0.6 M KCl is added. Samples are mixed carefully and fuged for 6 s at 1300 rpm, 4°C. The supernatant is discarded and the red blood cell lysis procedure is repeated one more time. Subsequently, the cell pellet is resuspended in 4 mL of DPBS and layered over 5 mL of Lymphoprep (Nycomed Pharma, Cat. N°.: 1114545) in a 15 mL centrifuge tube. After centrifugation for 12 min at 1300 rpm, 4°C, the supernatant is removed and the cell , containing the neutrophils, is resuspended in 25 mL chemotaxis buffer (RPMI 1640 medium, supplemented with 10 mM HEPES; freshly made for each experiment) 2. I .2 Migration assay
[00464] A cell suspension of 6 cells per milliliter is prepared. 20 uL of compound solution in chemotaxis buffer is added to 180 uL cell suspension. The mixture is incubated at 37°C for 30 minutes with intermediate resuspension of the cells after 15 minutes. Following this, 70 uL cell sion is transferred to the upper compartment of a Corning HTS transwell 96 permeable support system with 5.0 um pore size polycarbonate membrane (Corning, Cat.N°.: 3387). The receiver well of the transwell system is then filled with 200 uL chemotaxis buffer containing compound and chemotactic agent (embelin). After incubation at WO 92791 37°C in 5% C02 for 1 h, the upper plate of the transwell system is removed and the cell suspension in the er plate is transferred to a 96-well V-bottom plate. 50 uL of DPBS is added to the receiver plate to prevent remaining cells from drying out. The V-bottom plate is centrifuged for 6 minutes at 1500 rpm. The supernatant is removed and the cells are resuspended in 50 uL DPBS. The cells are then erred back to the receiver plate of the transwell system. After this, 100 uL ATPlite on (Perkin Elmer, Cat. N°: 436110) was added to the cells. The plate is incubated for 10 minutes in the dark, while shaking. 170 uL of cell lysate is then transferred to a white 96-well plate and luminescence is measured. The detected luminescent signal is considered as linearely related to the number of cells having migrated from the upper well to the receiver well.
TABLE VII: human neutro hil mi ration inhibition * > 1001 nM ** 501-1000 nM ***101-500 nM **** 0.01-100 nM de# Neutrophils de# Neutrophils *** **** *** **** *** **** “— **** **** **** **** **** **** **** **** **** *** **** *** **** **** **** **** m— **** **** **** m— **** m— **** **** **** de# Neutrophils de# Neutrophils — — 2.2. Rat neutrophil migration assay We have established that GPR84 agonists (MCFA such as sodiumdecanoate, 3,3 ’ di indolylmethane and Embelin induce neutrophil chemotaxis and that GPR84 antagonists could block GPR84 agonist-induced chemotaxis but not IL8-induced chemotaxis, indicating that G Protein-Coupled or 84 (GPR84) is an essential player in the s of neutrophil recruitment.
The effect of agonists or antagonists for GPR84 can therefore be assayed in a neutrophil migration test. In the rat neutrophil migration assay, neutrophils, freshly isolated from rat after intraperitoneal injection of glycogen (0.1 %, w/v), are d with a compound for 30 minutes. Subsequently, the neutrophils are transferred to the upper wells of a Corning HTS transwell 96 permeable support , of which the lower wells are filled with a embelin solution at EC80 (concentration which give 80% of the activity of the GPR84).
After 1 h of tion, ion of the neutrophils towards embelin in the lower compartment can be quantified by measuring the ntent of the lower wells using the Cell Titer Glow Substrate assay system (Promega, Cat.N°.: G755B). 2.2.1. Isolation ofneutrophilsfrom rats 24 h after intraperitoneal injection of glycogen (0.1 %, w/v), cells are harvested by peritoneal lavage with 25mL HBSS then centrifuged for 12 minutes at 1300 rpm and 4°C. After centrifiJgation, the supernatant is discarded and the remaining cell pellet is rapidly resuspended in 12 mL of ice-cold H20 for red blood cell lysis to occur. After 20 seconds, 4 mL of ice-cold 0.6 M KCl is added. Samples are mixed carefully and centrifuged for 6 minutes at 1300 rpm, 4°C. The supernatant is discarded and the cell pellet is ended in 4 mL of DPBS and layered over 5 mL of Lymphoprep (Axis Shield, Cat. N°.: 1114544) in a mL centrifuge tube. After centrifugation for 30 min at 1500 rpm, 4°C, the supernatant is removed and the cell pellet, containing the neutrophils, is resuspended in 5 mL chemotaxis buffer (RPMI 1640 medium, mented with 10 mM HEPES; y made for each experiment). 2.2.2. ion assay A cell suspension of 8.9x106 cells per milliliter is ed. 10 [LL of compound solution in chemotaxis buffer is added to 90 [LL cell suspension. The mixture is incubated at 37°C for 30 minutes with intermediate resuspension of the cells after 15 minutes. Following this, 75 [LL cell suspension is transferred to the upper tment of a Corning HTS transwell 96 permeable support system with 5.0 um pore size polycarbonate ne (Corning, Cat.N°.: 3387). The receiver well of the transwell system is then filled with 200 uL chemotaxis buffer ning compound and actic agent in). After incubation at 37°C in 5% C02 for 1 h, the upper plate of the transwell system is removed and 70 [LL Cell Titer Glow Substrate (Promega, Cat.N°.: G755B) are added in the receiver plate. The receiver plate is incubated for 10 minutes in the dark, while shaking. 180 uL of cell lysate is then erred to a white 96-well plate and scence is measured. The ed scent signal is considered as ely related to the number of cells having migrated from the upper well to the receiver well. 3. ADME, PK and Safety Models 3.] Aqueous Solubility Starting from a 10mM stock in DMSO, a serial dilution of the compound is prepared in DMSO.
The on series is transferred to a 96 NUNC Maxisorb plate F-bottom and 0.1M phosphate buffer pH 7.4 or 0.1M citrate buffer pH3.0 at room temperature is added.
The final concentrations range from 18.75 to 300 uM in 5 equal dilution steps. The final DMSO concentration does not exceed 3%. 200uM Pyrene is added to the comer points of each 96 well plate and serves as a reference point for calibration of Z-axis on the microscope.
The assay plates are sealed and incubated for 1 h at 37°C while shaking at 230rpm. The plates are then scanned under a white light microscope, yielding individual pictures of the precipitate per concentration.
The precipitate is analyzed and converted into a number by a custom-developed software tool. The first concentration at which the compound appears completely dissolved is the concentration reported, however the true concentration lies somewhere between this concentration and one dilution step higher.
Solubility values are reported in uM and in ug/mL. 3.2. Thermodynamic solubility Two individual solutions of 2 mg/mL of compound are prepared in a 0.1 M phosphate buffer pH 7.4 or a 0.1 M citrate buffer pH 3.0 at room temperature in a 2mL glass vial.
] After addition of a ic stir, the samples are stirred at room temperature for 24 h.
After 24 h, the vials are centrifuged 10 min at 1400 rpm. The supernatant of the sample is then transferred to a MultiscreenR Solubility Plate (Millipore, MSSLBPCS 0) and filtered (10-12" Hg) with the aid of a vacuum manifold into a clean Greiner polypropylene V-bottom 96 well plate. Per sample, two dilutions (factor 10 and 100) are made in DMSO. Other dilutions can be made if the acquired peak area is not within the standard curve.
A 10mM DMSO stock, made from dry matter, is used to make a 200ug/mL working stock. The standard curve for the compound is prepared in DMSO starting from the 200ug/mL working stock. Eight WO 92791 concentrations and two quality control samples (QC) are made in 2mL tubes. The first 3 concentrations (50, and 15 ug/mL) and the first QC sample (20ug/mL) are made starting with the 200ug/mL working stock.
The 4th concentration (5 ug/mL) is made with the 50ug/mL solution and the 5th concentration (1 ug/mL) with the 15ug/mL. The last three concentrations (0.2, 0.1 and 0.05 ug/mL) are made with the 1 ug/mL solution. The second QC sample (0.5ug/mL) is made with the first QC sample.
Of every step of the dilution series, quality control and sample dilutions, a volume is transferred to a 96-well Deepwell plate. The samples are injected on a LC-MS/MS system (API2000 from d Biosystems).
The s are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is 0.1% Formic Acid in methanol. The sample is run under positive ion spray on a Pursuit 5 C18 2.0mm column (Varian). The t nt has a total run time of 1.4 minutes and ranges from 10% B to 100% B.
] The thermodynamic solubility samples are analyzed with the aid of QuanLynx software. For the standard curve a linear or quadratic curve can be used in the analysis. Samples of the standard curve that have more than 15% deviation are excluded; the lowest concentrations of the curve may vary up to 20%. Peak areas of the samples are plotted against the standard curve to obtain the lity of the compound.
Solubility values are ed in uM or ug/mL. 3.3 Microsomal stability
[00483]A 10 mM stock solution of nd in DMSO is 1,668 fold diluted in a 105 mM phosphate buffer pH 7.4. Of this compound dilution, 50 [LL is transferred in two 96 assay plates: one for time point 0 min (T0 plate) and one for time point 30 min (T30 plate) and pre-warmed at 37°C.
In the time zero reference sample (T0 plate), 100 uL MeOH (1 :1) is added to the wells. In each assay plate (T0 and T30 min), 50 [LL of omal mix is then added.
[00485] Final reaction concentrations are: 3 uM compound, 0.5 mg/mL microsomes, 0.4 U/mL GDPDH, 3.3 mM MgC12, 3.3 mM glucosephosphate and 1.3 mM NADP+.
The T30 plate is incubated at 37°C, 300 rpm and after 30 minutes of incubation the reaction is stopped with MeOH (1 :1). The samples are mixed, centrifuged and the supernatant is ted for analysis on LC-MS/MS (API2000 from Applied Biosystems).
The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1% Formic Acid in water and t B is 0.1% Formic Acid in methanol. The sample is run under positive ion spray on a Pursuit 5 C18 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes and ranges from 10% B to 100% B.Peak area from the parent compound at time 0 is considered to be 100% remaining. The percentage remaining after 30 minutes incubation is ated from time 0 The solubility of the compound in the final test concentration in buffer is inspected by microscope and results are also 3.4 cyte stability.
Test compounds (1 uM initial concentration, n=2) are incubated in Williams’ Medium E, containing 4 mM L-gutamine and 2 mM magnesium sulphate, with pooled cryopreserved hepatocytes (Celsis International) in suspension at cell densities of 025-05 million viable cells/mL. The incubations are performed at 37°C in a shaking water bath with 100 uL samples taken from the incubation at 0, 10, 20, 45 and 90 minutes, and reactions terminated by addition of 100 uL of itrile containing carbamazepine as analytical internal standard. Samples are centrifuged and the supernatant fractions analysed by MS.
The instrument responses (Le. peak heights) are referenced to the zero time-point samples (as 100%) in order to determine the percentage of compound remaining. Ln plots of the % remaining for each compound are used to determine the half-life for the hepatocyte incubations. Half-life values are calculated from the onship: Tm (min) = -0.693/)t, where )t is the slope of the Ln concentration vs time curve. Standard compounds testosterone, midazolam, and 4-methylumbelliferone are ed in the assay design. 3.5 Plasma Protein Binding (Equilibrium Dialysis) A 10mM stock solution of the nd in DMSO is diluted with a factor 10 in DMSO. This solution is further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation INC) with a final concentration of 5 uM and final DMSO tration of 0.5%.
A Pierce Red Device plate with inserts (ThermoScientific) is prepared and filled with 450uL PBS in the buffer r and 300uL of the spiked plasma in the plasma chamber. The plate is ted for 4 h at 37°C While shaking at 100rpm. After incubation, 120uL of both rs is transferred to 480uL methanol in a 96-well round bottom, PP deep-well plates (Nunc) and sealed with an aluminum foil lid. The samples are mixed and immediately centrifuged 30 min at 1400 rcf at 4°C and the supernatant is erred to a 96 v-bottom PP plate (Greiner, 651201) for analysis on LC-MS/MS (API2000 from Applied Biosystems).
The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is 0.1% Formic Acid in methanol. The sample is run under ve ion spray on a Pursuit 5 C18 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes and ranges from 10% B to 100% B.
Peak area from the compound in the buffer chamber and the plasma chamber are considered to be 100% compound. The percentage bound to plasma is derived from these results and is reported as percentage bound to plasma.
The solubility of the compound in the final test concentration in PBS is inspected by microscope to indicate whether itation is observed or not. 3.6 CacoZ bility ectional Caco-2 assays are performed as described below. Caco-2 cells are obtained from European Collection of Cell Cultures (ECACC, cat 86010202) and used after a 21 day cell culture in 24-well Transwell plates (Corning, cell growth area: 033 cm2, Membrane pore size: 0.4 uM, membrane diameter: 6.5 mm).. 2x105 cells/well are seeded in plating medium ting of DMEM + GlutaMAXTM-I + 1% NEAA + 10% FBS (FetalClone II) + 1% Pen/Strep. The medium is changed every 2 — 3 days.
Test and reference compounds (propranolol and rhodamine123 or vinblastine, all purchased from Sigma) are prepared in Hanks’ Balanced Salt on containing 25 mM HEPES (pH7.4) and added to either the apical (125 uL) or teral (600uL) chambers of the Transwell plate assembly at a concentration of 10 uM with a final DMSO concentration of 0.25%.
[00497] 50uM Lucifer Yellow (Sigma) is added to the donor buffer in all wells to assess integrity of the cell layers by monitoring Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely permeate lipophilic barriers, a high degree of LY transport indicates poor integrity of the cell layer.
After a 1 h incubation at 37°C while shaking at an orbital shaker at 150rpm, 70uL aliquots are taken from both apical (A) and basal (B) chambers and added to 100uL 50:50 acetonitrile:water solution containing analytical internal standard (0.5uM azepine) in a 96 well plate. r yellow is measured with a Spectramax Gemini XS (Ex 426nm and Em 538nm) in a clean 96 well plate containing 150uL of liquid from basolateral and apical side.
Concentrations of compound in the samples are measured by high performance chromatography /mass spectroscopy (LC-MS/MS).
[00501] Apparent permeability (Papp) values are calculated from the relationship: Papp = [compound1acceptor final X Vacceptor / ([compound1donor initial X Vdonor) /Tinc X Vdonor / surface area X 60 X 10 cm/s V = chamber volume Tinc = incubation time. e area = 0.33cm2 The Efflux ratios, as an indication of active efflux from the apical cell surface, are calculated using the ratio of Papp B>A/ Papp A>B.
The ing assay acceptance ia are used: Propranolol: Papp (A>B) value 2 20(><10'6 cm/s) Rhodamine 123 or Vinblastine: Papp (A>B) value < 5 (><10'6 cm/s) with Efflux ratio 25.
Lucifer yellow permeability: £100 nm/s 3.7 Liabilityfor QTprolongation Potential for QT prolongation is assessed in the hERG manual patch clamp assay. 3. 7.1 Conventional whole-cellpalcn-clamp cell patch-clamp recordings are performed using an EPC10 amplifier controlled by Pulse V8.77 software (HEKA). Series resistance is typically less than 10 M9 and compensated by greater than 60%, recordings are not leak subtracted. Electrodes are manufactured from GC150TF pipette glass (Harvard).
The external bathing solution contains: 135 mM NaCl, 5 mM KCl, 1.8 mM CaClZ, 5 mM Glucose, mM HEPES, pH 7.4.
The al patch pipette solution ns: 100mM Kgluconate, 20 mM KCl, 1mM CaClZ, 1 mM MgC12, SmM NazATP, 2mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
[00508] Drugs are perfused using a Biologic EVH-9 rapid ion system.
All recordings are performed on HEK293 cells stably expressing hERG channels. Cells are cultured on 12 mm round lips (German glass, Bellco) anchored in the recording chamber using two platinum rods (Goodfellow). hERG currents are evoked using an activating pulse to +40 mV for 1000 ms followed by a tail current pulse to —50 mV for 2000 ms, holding potential is -80 mV. Pulses are applied every 20s and all experiments are med at room temperature. 3. 7.2 Data Analysis IC50 values are calculated for each compound tested. The fold difference n the IC50 in the manual hERG patch clamp and the d IC50 in the whole blood assay is calculated.
[00511] For the concentration response curves, peak tail current amplitude is measured during the voltage step to -50 mV. Curve-fitting of concentration-response data is performed using the equation: y=a+ [(b-a)/( 1+ 10A((10gC-X)d)] where a is minimum response, b is maximum response and d is Hill slope, this equation can be used to calculate both IC50 (where y = 50 and c is the IC50 value) and ICZO (where y = 20 and c is the ICZO value). ad® Prism® pad® Software Inc.) software is used for all curve g. A difference of 100 fold or greater indicates a low potential for QT prolongation. 3.8 Pharmacokinetic study 3.8.1 Single dose pharmacokinetic study in rats Compounds are ated in PEG200/physiological saline mixtures for the intravenous route and in PEG400/0.5% methylcellulose (10/90 v/v) for the oral route. Test compounds are orally dosed as a single esophageal gavage at 5-10 mg/kg and intravenously dosed as a bolus via the caudal vein at 1 mg/kg to male Sprague-Dawley rats. Each group consists of 3 rats. Blood samples are collected either via the jugular vein using cannulated rats or at the retro-orbital sinus with lithium heparin as anti-coagulant at the time points in the following range: 0.05 to 8 h (intravenous , and 0.25 to 6 or 24 h (oral route). Whole blood samples are centrifiJged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending analysis. 3.8.2 Multiple dose pharmacokinetic study in rats Compounds are formulated in PEG400/0.5% cellulose (10/90 v/v) for the oral route. Test compounds are orally dosed as an esophageal daily gavage at 30 or 300 mg/kg to male Sprague-Dawley rats for 14 days. Each group consists of 3 rats. Blood samples are collected via the tail vein with lithium heparin as oagulant at the following time points on day 1, 7 and 14: 0.25, 1, 4, 8 and 24 h. In addition, on day 2 blood samples are taken at 0.25, 1 and 4 h and at day 4 and 11 at 0.25 h. Whole blood s are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending is. 3.8.3 Quantification ofcompound levels in plasma
[00515] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode. 3.8.4 Determination ofpharmacokineticparameters Pharmacokinetic ters are calculated using Winnonlin® ight®, US). 3.9 7-Day rat toxicity study A 7-day oral toxicity study with test compounds is performed in Sprague-Dawley male rats to assess their toxic potential and toxicokinetics, at daily doses of 100, 300 and 1000 mg/kg/day, by gavage, at the constant dosage-volume of 10 mL/kg/day.
[00518] The test compounds are formulated in PEG400/0.5% methylcellulose (10/90, v/v). Each group includes 6 principal male rats as well as 3 satellite animals for toxicokinetics. A fourth group is given PEG400/0.5% methylcellulose (10/90, v/v) only, at the same frequency, dosage volume and by the same route of stration, and acts as the vehicle control group.
The goal of the study is to ine the lowest dose that results in no e events being identified (no observable adverse effect level - NOAEL). l 87 3.10 Cytochrome P450 inhibition Reversible CYP inhibition and ependent CYP3A4 inhibition is determined in human liver microsomes and specific probe substrates. 3.10.1 P450 inhibition in human liver microsomes, reversible inhibition The inhibitory ial of a test compound is assessed for human cytochrome P450 isoenzymes CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4.
A 10 mM stock solution of the test compound is prepared in DMSO, serially diluted in Tris buffer (100 mM pH 7.4) and added to hepatic microsomes (Xenotech LLC) and NADPH at 37°C in a shaking water bath. Seven different test nds concentrations (0.05 to 100 uM), 1% DMSO and 1 mM NADPH are obtained to react.
After 15 or 30 minutes reactions are terminated by on of 100 uL of acetonitrile containing carbamazepine as analytical al standard. Samples are centrifuged and the supernatant fractions analysed by MS. For each isoform, the instrument responses (peak heights) are referenced to those for DMSO controls (considered as 100%) in order to determine the percentage ion in probe metabolism, using midazolam and testosterone as probe substrate. Percentage inhibition of probe metabolism and Log [test compound concentration] are plotted using ad Prism software. The sigmoidal dose response model is fitted to the data in order to determine the IC50.
[00524] Inhibition of CYP3A4 using nifedipine and atorvastatin as probe substrate is carried out as follows.
] A 1.67 mM stock solution of test nd is prepared in methanol, serially diluted 1:3 in 50 mM potassium phosphate buffer pH7.4 and added to human hepatic microsomes (BD Gentest) and probe substrate. Seven different test compounds concentrations (0.045 - 33.3 uM), 2% methanol, 0.1 mg/mL omes, 10 uM atorvastatin or 5 uM nifedipine. After pre-warming 5 minutes at 37°C, the reaction was started by adding cofactor mix (7.65 mg/mL glucosephosphate, 1.7 mg/mL NADP, 6U/mL of e phosphate dehydrogenase).
After 5 min (nifedipine) or 10 min (atorvastatin) at 37°C, the reaction (50 uL) is terminated with 150 uL acetonitrile:methanol (2: 1) solution with internal standard (Warfarin). Samples are centrifuged and the supernatant fractions analyzed by LC-MS/MS. The instrument responses (ratio of test compound/internal standard peak areas) are referenced to those for solvent controls (assumed as 100%) in order to determine the tage reduction in probe metabolism. t of control activity vs tration plots are generated and fitted using GraphPad Prism software to generate IC50. 3.10.2 CYP3A4 inhibition in human liver microsomes, lime-dependent The time-dependent inhibitory ial of a test nd is assessed for human cytochrome P450 isoenzyme 3A4. The compound is pre-incubated with the human liver microsomes before addition of the probe substrates. The result is compared to the condition where the compound is not pre-incubated with the human liver omes to see if there was a shift in IC50, indicating time-dependent inhibition.
A 10 mM stock solution of test compound is prepared in DMSO and d 1:20 with Tris buffer (100 mM pH 7.4) and further serially diluted in Tris buffer/5% DMSO.
The cofactor, NADPH, and each test compound dilution is mixed in two separate plates for 0 and min pre-incubation. Human hepatic microsomes (Xenotech LLC) are added only to the “30 minute pre- incubation” plate and both plates are then incubated for 30 minutes at 37°C in a g water bath.
Following the pre-incubation, microsomes are added to the “0 minute” plate and riate probe ates (in 0.5% DMSO) are added to both plates. Plates are then returned to the water bath for a further incubation.
In total, six different test compound concentrations (1.6 to 50 uM) are assessed. Reactions are terminated with 100 uL of acetonitrile ning carbamazepine as analytical internal standard. Samples are centrifuged and the supernatant fractions analysed by LC- MS/MS. For each isoform, the instrument responses (peak height ratio with internal standard) are referenced to those for DMSO ls (considered as 100%) in order to determine the percentage reduction in probe lism. Percentage inhibition of probe metabolism and Log [Test Compound concentration] are plotted using Graphpad Prism software. The sigmoidal dose se model is fitted to the data in order to determine the IC50. 4. In-vivo s The in-viv0 activity ofthe compounds ofthe invention may be demonstrated in the following in vivo y inflammation models. 4.] Inflammatory bowel disease (mice).
The mouse chronic DSS—induced inflammatory bowel disease model (IBD) is a well validated disease model for inflammatory bowel disease (Wirtz S. et al., 2007 Nature Protocols 2, 541-546; Sina C. et al., 2009 J. Immunol. 183 7514-7522).
[00533] To induce a chronic colitis, female BALB/c mice are fed with 4% dextran sodium sulfate (DSS) dissolved in drinking water for 4 days, followed by 3 days of regular drinking water. This cycle is ed three times. This protocol allows inducing a strong colitis while avoiding high mortality rates. Animals are divided into several groups: a. intact water; e alone, n=10), b. diseased (DSS; vehicle alone, n=10), l 89 c. sulfazalazine used as reference (D88; 20 mg/kg/day, p.o., n=10) and d. the tested compound (D88; 1, 3, 10, 30 mg/kg/day,p.o., n=10).
Clinical parameters are ed every other day. The disease actiVity index (DAI) is a composite measure combining of the individual scores for weight loss, stool consistency and rectal bleeding. Mice are sacrificed at day 20 of the ment according to the ol introduced by Sina et al.(2009). At sacrifice time, the complete colon is removed and rinsed with sterile PBS.
Segments ofthe distal colon are dissected for histological is, gene expression and protein level measurement. 4.2 Collagen-induced arthritis (mice).
The mouse collagen-induced arthritis (CIA) is the gold standard toid tis model (Brand, er al., 2007 Nature Protocols 2, 1269- 1275, Lin er al., 2007 Br J Pharmacol 1, 829-831). DBA1//J male mice are injected with a collagen II solution (Completed Freund’s adjuvant). Immune reaction is boosted by a second injection plete Freund’s adjuvant) 21 days later. At day 31, arthritis is scored according to the method of Khachigian er al. (Khachigian er al., 2006 Nature Protocols 1, 2512-2516) and s are randomized to reach an average clinical score of 2 per group. Animals are divided into several groups: intact (no treatment, n=5), diseased le alone, n=10), Enbrel® as reference (10 mg/kg, 3x week, i.p., n=10), and the tested compound (3, 10 or 30 mg/kg/day, p.o., n=10). Therapeutic dosing lasted from day 31 to day 46 and the arthritis is scored every day. Mice are iced at day 46, X-ray photos are taken of the hind paws of each individual animal and the severity of bone erosion is ranked with the radiological Larsen’s score (Salvemini er al., 2001 Arthritis Rheum 44, 2909-2921). 4.3 Tabacco smoke model (mice) Daily exposures of female inbred C57BL/6J mice to tobacco smoke (TS) for 11 consecutive days result in pulmonary inflammation, as indicated by an increase in the total number of cells recovered in the bronchoalveolar lavage (BAL), when compared with a similarly d air-exposed group, 24 h after the final exposure. The exposure period to TS is increased initially from 25 minutes at the start of the study (day 1) to a maximum of 45 minutes on day 3 until day 11. Animals are diVided into several groups: intact (no ent, n=5), diseased (vehicle alone, n=10), Roflumilast as reference (5 mg/kg/day p.o., n=10), and the tested compounds (10 or 30 mg/kg/bid, p.o., n=10). At the end of 11 days, the numbers of macrophages, epithelial cells, phils and lymphocytes are counted in the BAL. BAL is further analysed for gene expression and protein level. Lung tissue is dissected for histological analysis, gene expression and protein level measurement.
It will be appreciated by those skilled in the art that the ing ptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through e experimentation, an artisan will recognise apparent modifications and variations that may be made t departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be d not by the above description, but by the following claims and their equivalents.
All ations, including but not d to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
It should be understood that factors such as the differential cell ation capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.
At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially ble chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
[00541] Chemical structures shown herein were prepared using either ChemDraw® or ISIS® /DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.
] The reference in this specification to any prior ation (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common l knowledge in the field of endeavour to which this specification relates.
[00543] Throughout this specification and the claims which follow, unless the context requires ise, the word "comprise", and variations such as "comprises" and ising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
NCES Wittenberger et al., 2001 J M01 Biol, 307, 799-813 Yousefi S et al., 2001 J Leukoc Biol, 69, 1045—52 Wang et al., 2006 The l of Biological Chemistry, 281 , 45, 34457-34464 Venkataraman et al., 2005, Immunology Letters, 101, 144-153 WO2007/027661 A2 Berry et al., 2010, , 466, 973-979 rd et al., 2007, Glia, 55:790-800 Bundgard, H., 1985 Design of Prodrugs, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985 Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania T. W. Greene and P. G. M. Wuts, 2006 Protecting Groups in c Synthesis, Wiley-Blackwell; 4th Revised edition Young Kim et al., 2007 Bioorganic & Medicinal Chemistry 15, 2667—2679 Le Pouls et al., 2003, The Journal of Biological Chemistry, 278, 28, 25481 -25489 Brown et al., 2003, The Journal ofBiological Chemistry, 278, 13, 11312-11319 Stoddart et al., 2008, Pharmacological Reviews, 60, 405-417 Wirtz S. et al., 2007 Nature Protocols 2, 541-546 Sina C. et al., 2009 J. Immunol. 183 7514-7522 Brand, et al., 2007 Nature Protocols 2, 1269- 1275 Lin et al., 2007 Br J col 1, 2 Khachigian et al., 2006 Nature Protocols 1 , 2512-2516 Salvemini et al., 2001 Arthritis Rheum 44, 2909-2921 Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129 Nagasaki et.al., 2012, FEBS Letters, 586, 368—372

Claims (1)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A nd according to Formula Ia: O N wherein 5 R1 is H, Me, or halo; L1 is absent or is –O-, -S-, or -NR4a-; G is -W-L2-R2, or 10 R3; W is C1-4 alkylene, C2-4 alkenylene having one double bond, or C2-4 lene having one triple bond; L2 is absent or is –O-; R2 is 15 - H, - C1-8 alkyl, optionally substituted with one to three groups independently selected from o OH, o halo, o CN, 20 o C1-6 alkoxy, o C3-7 cycloalkyl, o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O, o 5-6 membered heteroaryl comprising one to three heteroatoms independently 25 selected from N, S, and O, and o phenyl, - C4-7 cycloalkenyl comprising one double bond, H:\rbr\Interwoven\NRPortbl\DCC\RBR\9599805_1.docx-
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US201161578979P 2011-12-22 2011-12-22
US61/578,979 2011-12-22
PCT/EP2012/076275 WO2013092791A1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders

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NZ626473B2 true NZ626473B2 (en) 2016-07-01

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